Quinazoline derivatives as antitumor agents

ABSTRACT

A quinazoline derivative of the formula (I): (A chemical formula should be inserted here—please see paper copy enclosed) Formula I wherein the substituents are as defined in the text for use in the production of an anti proliferative effect which effect is produced alone or in part by inhibiting erbB2 receptor tyrosine kinase in a warm blooded animal such as man.

The invention concerns certain novel quinazoline derivatives, orpharmaceutically-acceptable salts thereof, which possess anti-tumouractivity and are accordingly useful in methods of treatment of the humanor animal body. The invention also concerns processes for themanufacture of said quinazoline derivatives, to pharmaceuticalcompositions containing them and to their use in therapeutic methods,for example in the manufacture of medicaments for use in the preventionor treatment of solid tumour disease in a warm-blooded animal such asman.

Many of the current treatment regimes for diseases resulting from theabnormal regulation of cellular proliferation such as psoriasis andcancer, utilise compounds that inhibit DNA synthesis and cellularproliferation. To date, compounds used in such treatments are generallytoxic to cells however their enhanced effects on rapidly dividing cellssuch as tumour cells can be beneficial. Alternative approaches to thesecytotoxic anti-tumour agents are currently being developed, for exampleselective inhibitors of cell signalling pathways. These types ofinhibitors are likely to have the potential to display an enhancedselectivity of action against tumour cells and so are likely to reducethe probability of the therapy possessing unwanted side effects.

Eukaryotic cells are continually responding to many diverseextracellular signals that enable communication between cells within anorganism. These signals regulate a wide variety of physical responses inthe cell including proliferation, differentiation, apoptosis andmotility. The extracellular signals take the form of a diverse varietyof soluble factors including growth factors as well as paracrine andendocrine factors. By binding to specific transmembrane receptors, theseligands integrate the extracellular signal to the intracellularsignalling pathways, therefore transducing the signal across the plasmamembrane and allowing the individual cell to respond to itsextracellular signals. Many of these signal transduction processesutilise the reversible process of the phosphorylation of proteins thatare involved in the promotion of these diverse cellular responses. Thephosphorylation status of target proteins is regulated by specifickinases and phosphatases that are responsible for the regulation ofabout one third of all proteins encoded by the mammalian genome. Asphosphorylation is such an important regulatory mechanism in the signaltransduction process, it is therefore not surprising that aberrations inthese intracellular pathways result in abnormal cell growth anddifferentiation and so promote cellular transformation (reviewed inCohen et al, Curr Opin Chem Biol, 1999, 3, 459-465).

It has been widely shown that a number of these tyrosine kinases aremutated to constitutively active forms and/or when over-expressed resultin the transformation of a variety of human cells. These mutated andover-expressed forms of the kinase are present in a large proportion ofhuman tumours (reviewed in Kolibaba et al, Biochimica et BiophysicaActa, 1997, 133, F217-F248). As tyrosine kinases play fundamental rolesin the proliferation and differentiation of a variety of tissues, muchfocus has centred on these enzymes in the development of novelanti-cancer therapies. This family of enzymes is divided into twogroups—receptor and non-receptor tyrosine kinases e.g. EGF Receptors andthe SRC family respectively. From the results of a large number ofstudies including the Human Genome Project, about 90 tyrosine kinasehave been identified in the human genome, of this 58 are of the receptortype and 32 are of the non-receptor type. These can be compartmentalisedin to 20 receptor tyrosine kinase and 10 non-receptor tyrosine kinasesub-families (Robinson et al, Oncogene, 2000, 19, 5548-5557).

The receptor tyrosine kinases are of particular importance in thetransmission of mitogenic signals that initiate cellular replication.These large glycoproteins, which span the plasma membrane of the cellpossess an extracellular binding domain for their specific ligands (suchas Epidermal Growth Factor (EGF) for the EGF Receptor). Binding ofligand results in the activation of the receptor's kinase enzymaticactivity that is encoded by the intracellular portion of the receptor.This activity phosphorylates key tyrosine amino acids in targetproteins, resulting in the transduction of proliferative signals acrossthe plasma membrane of the cell.

It is known that the erbB family of receptor tyrosine kinases, whichinclude EGFR, erbB2, erbB3 and erbB4, are frequently involved in drivingthe proliferation and survival of tumour cells (reviewed in Olayioye etal., EMBO J., 2000, 19, 3159). One mechanism in which this can beaccomplished is by overexpression of the receptor at the protein level,generally as a result of gene amplification. This has been observed inmany common human cancers (reviewed in Klapper et al., Adv. Cancer Res.,2000, 77, 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer,1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al.,Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994,29, 73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol., 1995,19, 183), non-small cell lung cancers (NSCLCs) including adenocarcinomas(Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al. Int. J.Cancer, 1990, 45, 269; Rusch et al., Cancer Research, 1993, 53, 2379;Brabender et al, Clin. Cancer Res., 2001, 7, 1850) as well as othercancers of the lung (Hendler et al., Cancer Cells, 1989, 7, 347; Ohsakiet al., Oncol. Rep., 2000, 7, 603), bladder cancer (Neal et al., Lancet,1985, 366; Chow et al., Clin. Cancer Res., 2001, 7, 1957, Zhau et al.,Mol Carcinog., 3, 254), oesophageal cancer (Mukaida et al., Cancer,1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomachcancer (Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al.,Gastroenterology, 2000, 112, 1103; Ross et al., Cancer Invest., 2001,19, 554), cancer of the prostate (Visakorpi et al., Histochem. J., 1992,24, 481; Kumar et al., 2000, 32, 73; Scher et al., J. Natl. CancerInst., 2000, 92, 1866), leukaemia (Konaka et al., Cell, 1984, 37, 1035,Martin-Subero et al., Cancer Genet Cytogenet., 2001, 127, 174), ovarian(Hellstrom et al., Cancer Res., 2001, 61, 2420), head and neck (Shiga etal., Head Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et al.,Neoplasma, 2001, 48, 188). As more human tumour tissues are tested forexpression of the erbB family of receptor tyrosine kinases it isexpected that their widespread prevalence and importance will be furtherenhanced in the future.

As a consequence of the mis-regulation of one or more of these receptors(in particular erbB2), it is widely believed that many tumours becomeclinically more aggressive and so correlate with a poorer prognosis forthe patient (Brabender et al, Clin. Cancer Res., 2001, 7, 1850; Ross etal, Cancer Investigation, 2001, 19, 554, Yu et al., Bioessays, 2000,22.7, 673). In addition to these clinical findings, a wealth ofpre-clinical information suggests that the erbB family of receptortyrosine kinases are involved in cellular transformation. This includesthe observations that many tumour cell lines overexpress one or more ofthe erbB receptors and that EGFR or erbB2 when transfected intonon-tumour cells have the ability to transform these cells. Thistumourigenic potential has been further verified as transgenic mice thatoverexpress erbB2 spontaneously develop tumours in the mammary gland. Inaddition to this, a number of pre-clinical studies have demonstratedthat anti-proliferative effects can be induced by knocking out one ormore erbB activities by small molecule inhibitors, dominant negatives orinhibitory antibodies (reviewed in Mendelsohn et al., Oncogene, 2000,19, 6550). Thus it has been recognised that inhibitors of these receptortyrosine kinases should be of value as a selective inhibitor of theproliferation of mammalian cancer cells (Yaish et al. Science, 1988,242, 933, Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133,F217-F248; Al-Obeidi et al, 2000, Oncogene, 19, 5690-5701; Mendelsohn etal, 2000, Oncogene, 19, 6550-6565). In addition to this pre-clinicaldata, findings using inhibitory antibodies against EGFR and erbB2 (c-225and trastuzumab respectively) have proven to be beneficial in the clinicfor the treatment of selected solid tumours (reviewed in Mendelsohn etal, 2000, Oncogene, 19, 6550-6565).

Amplification and/or activity of members of the ErbB type receptortyrosine kinases have been detected and so have been implicated to playa role in a number of non-malignant proliferative disorders such aspsoriasis (Ben-Bassat, Curr. Pharm. Des., 2000, 6, 933; Elder et al.,Science, 1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar etal., Int. Urol. Nephrol., 2000, 32, 73), atherosclerosis and restenosis(Bokemeyer et al., Kidney Int., 2000, 58, 549). It is therefore expectedthat inhibitors of erbB type receptor tyrosine kinases will be useful inthe treatment of these and other non-malignant disorders of excessivecellular proliferation.

International Patent Applications WO 96/09294, WO 96/15118, WO 96/16960,WO 96/30347, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO96/33981, WO 97/03069, WO 97/13771, WO 97/30034, WO 97/30035, WO97/38983, WO 98/02437, WO 98/02434, WO 98/02438, WO 98/13354, WO99/35132, WO 99/35146, WO01/21596, WO 01/55141 and WO 02/18372 disclosethat certain quinazoline derivatives which bear an anilino substituentat the 4-position possess receptor tyrosine kinase inhibitory activity.

International Patent Applications WO01/94341 discloses that certainquinazoline derivatives which carry a 5-substituent are inhibitors ofthe Src family of non-receptor tyrosine kinases, such as c-Src, c-Yesand c-Fyn.

International Patent applications WO03/040108 and WO03/040109 disclosethat certain quinazoline derivatives which carry a 5-substituent areinhibitors of the erbB family of tyrosine kinase inhibitors,particularly EGFR and erb-B2 receptor tyrosine kinases.

We have now found that surprisingly certain quinazoline derivativessubstituted at the 5-position with a substituent containing certainsubstituted alkanoyl groups possess potent anti-tumour activity. Withoutwishing to imply that the compounds disclosed in the present inventionpossess pharmacological activity only by virtue of an effect on a singlebiological process, it is believed that the compounds provide ananti-tumour effect by way of inhibition of one or more of the erbBfamily of receptor tyrosine kinases that are involved in the signaltransduction steps which lead to the proliferation of tumour cells. Inparticular, it is believed that the compounds of the present inventionprovide an anti-tumour effect by way of inhibition of EGFR and/or erbB2receptor tyrosine kinases.

Generally the compounds of the present invention possess potentinhibitory activity against the erbB receptor tyrosine kinase family,for example by inhibition of EGFR and/or erbB2 and/or erbB4 receptortyrosine kinases, whilst possessing less potent inhibitory activityagainst other kinases. Furthermore, generally the compounds of thepresent invention possess substantially better potency against the erbB2over that of the EGFR tyrosine kinase, thus potentially providingeffective treatment for erbB2 driven tumours. Accordingly, it may bepossible to administer a compound according to the present invention ata dose that is sufficient to inhibit erbB2 tyrosine kinase whilst havingno significant effect upon EGFR (or other) tyrosine kinases. Theselective inhibition provided by the compounds according to the presentinvention may provide treatments for conditions mediated by erbB2tyrosine kinase, whilst reducing undesirable side effects that may beassociated with the inhibition of other tyrosine kinases.

Generally the compounds according to the invention exhibit favourableDMPK properties, for example high bioavailability and/or highfree-plasma levels.

According to a first aspect of the invention there is provided aquinazoline derivative of the Formula I:

wherein:

R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, S, SO, SO₂, N(R³), CO, CON(R³), N(R³)CO,SO₂N(R³) and N(R³)SO₂, wherein R³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino;

Y is selected from hydrogen, halogeno, (1-C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl and (2-4C)alkynyl;

a is 0, 1, 2 or 3 or 4;

each R², which may be the same or different, is selected from halogeno,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;

X² is a direct bond or is selected from O, S, OC(R⁴)₂, SC(R⁴)₂, SO, SO₂,N(R⁴), CO and N(R⁴)C(R⁴)₂ wherein each R⁴, which may be the same ordifferent, is selected from hydrogen or (1-6C)alkyl, and Q² is aryl orheteroaryl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl,mercapto, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alknoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵

wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶), whereinR⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl,N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within —X²-Q² optionally bears on eachsaid CH₂ or CH₃ one or more (for example 1, 2, or 3) halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

X¹ is a direct bond or C(R⁷)₂, wherein each R⁷, which may be the same ordifferent, is selected from hydrogen and (1-4C)alkyl;

ring Q¹ is a 4, 5, 6 or 7 membered saturated or partially unsaturatedheterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or2 additional heteroatoms selected from O, S and N, and which ring islinked to the group X¹ by a ring carbon;

X³ is a group of the formula:—(CR⁸R⁹)_(p)-(Q³)_(m)-(CR¹⁰R¹¹)_(q)—

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4,

each of R⁸, R⁹, R¹⁰ and R¹¹, which may be the same or different, isselected from hydrogen and (1-6C)alkyl, and

Q³ is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene;

Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:Q⁴-X⁵—

wherein X⁵ is a direct bond or is selected from O, N(R¹²), SO₂ andSO₂N(R¹²), wherein R¹² is hydrogen or (1-6C)alkyl, and Q⁴ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁵ is a direct bond, Q⁴ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Zsubstituent are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹³), CO, —C═C— and —C≡C— whereinR¹³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within any Z, X¹ or X³ group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group represented by Q¹ or within a Zsubstituent optionally bears one or more (for example 1, 2 or 3)substituents which may be the same or different, selected from halogeno,trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto,(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group represented by Q¹ or within a Zsubstituent optionally bears 1 or 2 oxo or thioxo substituents;

or a pharmaceutically acceptable salt thereof.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups such as propyl, isopropyland tert-butyl, and (3-7C)cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However referencesto individual alkyl groups such as “propyl” are specific for thestraight-chain version only, references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only and references to individual cycloalkyl groups such as“cyclopentyl” are specific for that 5-membered ring only. An analogousconvention applies to other generic terms, for example (1-6C)alkoxyincludes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy,(1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino andcyclohexylamino, and di-[(1-6Calkyl]amino includes dimethylamino,diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the above-mentioned activity. It is further to be understoodthat in the names of chiral compounds (R,S) denotes any scalemic orracemic mixture while (R) and (S) denote the enantiomers. In the absenceof (R,S), (R) or (S) in the name it is to be understood that the namerefers to any scalemic or racemic mixture, wherein a scalemic mixturecontains R and S enantiomers in any relative proportions and a racemicmixture contains R and S enantiomers in the ratio 50:50. The synthesisof optically active forms may be carried out by standard techniques oforganic chemistry well known in the art, for example by synthesis fromoptically active starting materials or by resolution of a racemic form.Similarly, the above-mentioned activity may be evaluated using thestandard laboratory techniques referred to hereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for any one of the ‘Q’ groups (for example Q²) when itis aryl or for the aryl group within a ‘Q’ group is, for example, phenylor naphthyl, preferably phenyl.

A suitable value for any one of the ‘Q’ groups (for example Q⁴) when itis (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a ‘Q’ groupor a R¹ group is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value forany one of the ‘Q’ groups (for example Q¹) when it is (3-7C)cycloalkenylor for the (3-7C)cycloalkenyl group within a ‘Q’ group is, for example,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. It is to beunderstood that reference to (3-7C)cycloalkylene used herein for Q³refers to a divalent (3-7C)cycloalkane linking group, which group may belinked via different carbon atoms in the (3-7C)cycloalkylene ring, orwhich may be linked via a single carbon atom in the (3-7C)cycloalkylenering. Accordingly, reference to, for example, a “cyclopropylene” groupincludes cycloprop-1,2-ylene and a cyclopropylidene group of theformula:

wherein * represent the bonds from the divalent cyclopropylidene group.

However references to an individual (3-7C)cycloalkylene group such ascyclopropylidene are specific for that group only. A similar conventionis adopted for the (3-7C)cycloalkenylene groups represented by Q³.

References to (3-7C)cycloalkyl-oxy groups include, for example,cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy, cyclohexyl-oxy,cycloheptyl-oxy or bicyclo[2.2.1]heptyl-oxy. References to(3-7C)cycloalkyl-(1-6C)alkoxy groups include, for example,cyclopropyl-(1-6C)alkoxy, cyclobutyl-(1-6C)alkoxy,cyclopentyl-(1-6C)alkoxy, cyclohexyl-(1-6C)alkoxy,cycloheptyl-(1-6C)alkoxy or bicyclo[2.2.1]heptyl-(1-6C)alkoxy, where the(1-6C)alkoxy group may be, for example, methoxy, ethoxy, propoxy,isopropoxy or butoxy. Particular values for(3-7C)cycloalkyl-(1-6C)alkoxy groups include, for example,cyclopropylmethoxy and cyclopropylethoxy.

A suitable value for any one of the ‘Q’ groups (for example Q²) when itis heteroaryl or for the heteroaryl group within a ‘Q’ group is, forexample, an aromatic 5- or 6-membered monocyclic ring or a 9- or10-membered bicyclic ring with up to five ring heteroatoms independentlyselected from oxygen, nitrogen and sulfur, for example furyl, pyrrolyl,thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, 1,3-benzodioxolyl,benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl,quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl. A particularvalue for any one of the ‘Q’ groups (for example Q²) when it isheteroaryl or for the heteroaryl group within a ‘Q’ group is, forexample, an aromatic 5- or 6-membered monocyclic ring with up to four(for example 1, 2 or 3) ring heteroatoms independently selected fromoxygen, nitrogen and sulfur, for example furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl or 1,3,5-triazenyl. A further particular valuefor any one of the ‘Q’ groups (for example Q²) when it is heteroaryl orfor the heteroaryl group within a ‘Q’ group is, for example, an aromatic5- or 6-membered monocyclic ring containing nitrogen and, optionally,one or two (for example one) additional ring heteroatoms independentlyselected from oxygen, nitrogen and sulfur, for example pyrrolyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl or 1,3,5-triazenyl.

A suitable value for any one of the ‘Q’ groups (for example Q¹ or Q⁴)when it is heterocyclyl or for the heterocyclyl group within a ‘Q’ groupis, for example, a non-aromatic saturated (i.e. ring systems with themaximum degree of saturation) or partially saturated (i.e. ring systemsretaining some, but not the full, degree of unsaturation) 3 to 10membered monocyclic or bicyclic ring with up to five heteroatomsindependently selected from oxygen, nitrogen and sulfur, which, unlessspecified otherwise, may be carbon or nitrogen linked, for exampleoxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl,morpholinyl, tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl,tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl,particularly tetrahydrofuranyl, tetrahydropyranyl pyrrolidinyl,morpholinyl, 1,4-oxazepanyl, thiamorpholinyl1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl, moreparticularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl,tetrahydrothien-3-yl, tetrahydrothiopyran-4-yl, pyrrolidin-1-ylpyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl,piperidino, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl orpiperazin-1-yl. A nitrogen or sulfur atom within a heterocyclyl groupmay be oxidized to give the corresponding N or S oxide, for example1,1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl,1,1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. A suitablevalue for such a group which bears 1 or 2 oxo or thioxo substituents is,for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for any one of the ‘Q’ groups (for example Q¹) when itis a nitrogen containing heterocyclyl group is, for example, anon-aromatic saturated or partially saturated 3 to 10 memberedmonocyclic or bicyclic ring with up to five heteroatoms independentlyselected from oxygen, nitrogen and sulfur, provided at least oneheteroatom is nitrogen, which, unless specified otherwise, may be carbonor nitrogen linked. Suitable values include, for example, thoseheterocyclic groups mentioned above that contain at least one nitrogenatom, for example azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl(including morpholino), tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl (including piperidino),homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl,tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,decahydroisoquinolinyl or decahydroquinolinyl.

Particular values for Q¹ is a carbon linked 4, 5, 6 or 7 memberedmonocyclic heterocyclyl group containing 1 nitrogen heteroatom andoptionally 1 or 2 further heteroatoms independently selected fromoxygen, nitrogen and sulfur, which heterocyclyl group may be fullysaturated or partially saturated. More particularly Q¹ is a carbonlinked 5 or 6 membered monocyclic heterocyclyl group containing 1nitrogen heteroatom and optionally 1 further heteroatom selected fromoxygen, nitrogen and sulfur, which heterocyclyl group may be partiallysaturated or preferably fully saturated. Still more particularly Q¹ is acarbon linked monocyclic fully saturated 5 or 6 membered monocyclicheterocyclyl group containing 1 nitrogen heteroatom and optionally 1further heteroatom selected from oxygen, nitrogen and sulfur. Suitablevalues of such groups represented by Q¹ include the appropriateheterocyclyl groups listed above, more particularly azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (all of which arelinked to X¹ by a ring carbon), more particularly, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidinyl, piperidin-3-yl, piperidin-2-yl,piperazin-2-yl, piperazin-3-yl, morpholin-2-yl or morpholin-3-yl, andstill more particularly pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-3-yl, piperidin-2-yl, piperazin-2-yl, piperazin-3-yl,morpholin-2-yl or morpholin-3-yl.

For the avoidance of any doubt the nitrogen atom in Q¹ to which thegroup ZX³C(O) is attached is not quaternised; namely the group ZX³C(O)is attached to the nitrogen atom in Q¹ via substitution of an NH groupin the heterocyclyl ring, for example when Q¹ is pyrrolidin-2-yl theZX³C(O) group is attached to the pyrrolidin-2-yl ring at the 1-position.

A suitable value for a ‘Q’ group when it is heterocyclyl-(1-6C)alkyl is,for example, heterocyclylmethyl, 2-heterocyclylethyl and3-heterocyclylpropyl. The invention comprises corresponding suitablevalues for ‘Q’ groups when, for example, rather than aheterocyclyl-(1-6C)alkyl group, an (3-7C)cycloalkyl-(1-6C)alkyl or(3-7C)cycloalkenyl-(1-6C)alkyl is present.

Suitable values for any of the ‘R’ groups (R¹ to R¹³), Y, or for variousgroups within a Q¹, Q², X³ or Z group include:—

-   for halogeno fluoro, chloro, bromo and iodo;-   for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;-   for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl;-   for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl;-   for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;-   for (2-6C)alkenyloxy: vinyloxy and allyloxy;-   for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy;-   for (1-6C)alkylthio: methylthio, ethylthio and propylthio;-   for (1-6C)alkylsulfinyl: methylsulfinyl and ethylsulfinyl;-   for (1-6C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl;-   for (1-6C)alkylamino: methylamino, ethylamino, propylamino,    isopropylamino and butylamino;-   for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino,    N-ethyl-N-methylamino and diisopropylamino;-   for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,    propoxycarbonyl and tert-butoxycarbonyl;-   for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and    N-propylcarbamoyl;-   for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,    N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;-   for (2-6C)alkanoyl: acetyl, propionyl, butyryl and isobuyryl;-   for (2-6C)alkanoyloxy: acetoxy and propionyloxy;-   for (2-6C)alkanoylamino: acetamido and propionamido;-   for N-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and    N-methylpropionamido;-   for N-(1-6C)alkylsulfamoyl: N-methylsulfamoyl and N-ethylsulfamoyl;-   for N,N-di-[(1-6C)alkyl]sulfamoyl: N,N-dimethylsulfamoyl;    for (1-6C)alkanesulfonylamino: methanesulfonylamino and    ethanesulfonylamino;-   for N-(1-6C)alkyl-(1-6C)alkanesulfonylamino:    N-methylmethanesulfonylamino and N-methylethanesulfonylamino;-   for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido;-   for N-(1-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and    N-methylcrotonamido;-   for (3-6C)alkynoylamino: propiolamido;-   for N-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido;-   for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and    3-aminopropyl;-   for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl,    ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,    2-ethylaminoethyl and 3-methylaminopropyl;-   for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,    diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and    3-dimethylaminopropyl;-   for halogeno-(1-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl    and 3-chloropropyl;-   for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl,    1-hydroxyethyl and 3-hydroxypropyl;-   for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,    1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;-   for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and    3-cyanopropyl;-   for (1-6C)alkylthio-(1-6C)alkyl: methylthiomethyl, ethylthiomethyl,    2-methylthioethyl, 1-methylthioethyl and 3-methylthiopropyl;-   for (1-6C)alkylsulfinyl-(1-6C)alkyl: methylsulfinylmethyl,    ethylsulfinylmethyl, 2-methylsulfinylethyl, 1-methylsulfinylethyl    and 3-methylsulfinylpropyl;-   for (1-6C)alkylsulfonyl-(1-6C)alkyl: methylsulfonylmethyl,    ethylsulfonylmethyl, 2-methylsulfonylethyl, 1-methylsulfonylethyl    and 3-methylsulfonylpropyl;-   for (2-6C)alkanoylamino-(1-6C)alkyl: acetamidomethyl,    propionamidomethyl and 2-acetamidoethyl;-   for N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl:    N-methylacetamidomethyl, 2-(N-methylacetamido)ethyl and    2-(N-methylpropionamido)ethyl;-   for (1-6C)alkoxycarbonylamino-(1-6C)alkyl:    methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl,    tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl;-   for (2-6C)alkanoyloxy-(1-6C)alkyl: acetoxymethyl, 2-acetoxyethyl and    2-propionyloxyethyl;-   for carbamoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl,    2-carbamoylethyl and 3-carbamoylpropyl;-   for (2-6C)alkanoyl-(1-6C)alkyl: acetylmethyl and 2-acetylethyl;-   for N-(1-6C)alkylcarbamoyl-(1-6C)alkyl: N-methylcarbamoylmethyl,    N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,    1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,    2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and    3-(N-methylcarbamoyl)propyl;-   or N,N-di[(1-6C)alkyl]carbamoyl-(1-6C)alkyl:    N,N-dimethylcarbamoylmethyl, N,N-diethylcarbamoylmethyl,    2-(N,N-dimethylcarbamoyl)ethyl, and 3-(N,N-dimethylcarbamoyl)propyl;-   for sulfamoyl(1-6C)alkyl: sulfamoylmethyl, 1-sulfamoylethyl,    2-sulfamoylethyl and 3-sulfamoylpropyl;-   for N-(1-6C)alkylsulfamoyl(1-6C)alkyl: N-methylsulfamoylmethyl,    N-ethylsulfamoylmethyl, N-propylsulfamoylmethyl,    1-(N-methylsulfamoyl)ethyl, 2-(N-methylsulfamoyl)ethyl and    3-(N-methylsulfamoyl)propyl;-   for N,N di-(1-6C)alkylsulfamoyl(1-6C)alkyl:    N,N-dimethylsulfamoylmethyl, N,N-diethylsulfamoylmethyl, N-methyl,    N-ethylsulfamoylmethyl, 1-(N,N-dimethylsulfamoyl)ethyl,    1-(N,N-diethylsulfamoyl)ethyl, 2-(N,N-dimethylsulfamoyl)ethyl,    2-(N,N-diethylsulfamoyl)ethyl and 3-(N,N-dimethylsulfamoyl)propyl;-   for carboxy-(1-6C)alkyl: carboxymethyl, 2-carboxyethyl,    1-carboxyethyl and 3-carboxypropyl; and-   for (1-6C)alkoxycarbonyl-(1-6C)alkyl methoxycarbonylmethyl,    ethoxycarbonylmethyl, tert-butoxycarbonylmethyl and    2-methoxycarbonylethyl.

When, as defined hereinbefore, in the group of the formula —X²-Q², X²is, for example, a OC(R⁴)₂ linking group, it is the oxygen atom, not thecarbon atom, of the OC(R⁴)₂ linking group which is attached to thephenyl ring in the Formula I and the carbon atom is attached to the Q²group. Similarly when X² is a N(R⁴)C(R⁴)₂ linking group the nitrogenatom of the N(R⁴)C(R⁴)₂ group is attached to the phenyl ring in FormulaI and the nitrogen atom is attached to the Q² group. A similarconvention is applied to other linking groups used herein, for examplewhen Z is a group of the formula Q⁴-X⁵—, and X⁵ is SO₂N(R¹⁰), the SO₂group is attached to Q⁴ and the nitrogen atom is attached to X³ inFormula I. Similarly, when X³ is Q³-(CR⁸R⁹)_(m), the Q³ is attached tothe group Z in Formula I and the (CR⁸R⁹)_(m) group is attached to thecarbonyl group in Formula I.

It is to be understood that references herein to adjacent carbon atomsin any (2-6C)alkylene chain within a group may be optionally separatedby the insertion into the chain of a group such as O or C≡C refer toinsertion of the specified group between two carbon atoms in an alkylenechain. For example, when Z is a 2-pyrrolidin-1-ylethoxy group insertionof a C≡C group into the ethylene chain gives rise to a4-pyrrolidin-1-ylbut-2-ynyloxy group.

When reference is made herein to a CH₂ or CH₃ group optionally bearingon each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, there are suitably 1 or 2 halogeno or (1-6C)alkylsubstituents present on each said CH₂ group and there are suitably 1, 2or 3 such substituents present on each said CH₃ group.

Where reference is made herein to any CH₂ or CH₃ group optionallybearing on each said CH₂ or CH₃ group a substituent as defined herein,suitable substituents so formed include, for example,hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy,hydroxy-substituted heterocyclyl-(1-6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl,2-hydroxypropionyl and 2-hydroxybutyryl.

It is to be understood that certain compounds of the Formula I may existin solvated as well as unsolvated forms such as, for example, hydratedforms. It is to be understood that the invention encompasses all suchsolvated forms which exhibit an inhibitory effect on an erbB receptortyrosine kinase.

It is also to be understood that certain compounds of the Formula I mayexhibit polymorphism, and that the invention encompasses all such formswhich exhibit an inhibitory effect on an erbB receptor tyrosine kinase.

It is also to be understood that the invention relates to all tautomericforms of the compounds of the Formula I forms which exhibit aninhibitory effect on an erbB receptor tyrosine kinase.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula I,for example an acid-addition salt with an inorganic or organic acid suchas hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric ormaleic acid; or, for example, a salt of a compound of the Formula Iwhich is sufficiently acidic, for example an alkali or alkaline earthmetal salt such as a calcium or magnesium salt, or an ammonium salt, ora salt with an organic base such as methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example,quinazoline derivatives of the Formula I, or pharmaceutically-acceptablesalts thereof, wherein, unless otherwise stated, each of R¹, R², Q¹, Q²,X¹, X², X³, Y, a and Z has any of the meanings defined hereinbefore orin paragraphs (a) to (xxxxxxxx) hereinafter:—

(a) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, sulfamoyl, oxo, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl andN,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino;

(b) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, or a substituent selected from hydroxy, cyano, amino,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino;

(c) R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy, amino,(1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

(d) R¹ is selected from hydrogen, (1-6C)alkoxy,cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy,cyclopentyl-(1-4C)alkoxy and cyclohexyl-(1-6C)alkoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy, methoxy andethoxy;

(e) R¹ is selected from hydrogen, (1-6C)alkoxy, cyclopropylmethoxy and2-cyclopropylethoxy,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more fluoro or chlorosubstituents, or a substituent selected from hydroxy, methoxy andethoxy;

(f) R¹ is selected from hydrogen, methoxy, ethoxy, propyloxy,isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy,2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and2,2,2-trifluoroethoxy;

(g) R¹ is selected from hydrogen and (1-3C)alkoxy;

(h) R¹ is hydrogen;

(i) R¹ is methoxy;

(j) Y is selected from hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy and(2-4C)alkynyl;

(k) Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl and (2-4C)alkynyl;

(l) Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy and(2-4C)alkynyl;

(m) Y is selected from hydrogen, halogeno, (1-4C)alkoxy and(2-4C)alkynyl;

(n) Y is selected from hydrogen, halogeno and (1-4C)alkyl;

(o) Y is selected from hydrogen and halogeno;

(p) Y is selected from halogeno and (1-4C)alkyl;

(q) Y is halogeno;

(r) Y is (1-4C)alkyl (particularly (1-2C)alkyl);

(s) Y is selected from hydrogen, fluoro, chloro, methyl, methoxy andethynyl;

(t) Y is selected from hydrogen, fluoro, chloro and methyl;

(u) Y is selected from hydrogen, fluoro, chloro and bromo;

(v) Y is selected from hydrogen, chloro and methyl;

(w) Y is selected from hydrogen and chloro;

(x) Y is selected from chloro and methyl;

(y) Y is hydrogen;

(z) Y is chloro;

(aa) Y is methyl;

(bb) a is 0, 1 or 2 and each R², which may be the same or different, isselected from halogeno;

(cc) a is 0 or 1 and R² is selected from fluoro and chloro;

(dd) a is 0;

(ee) a is 0 and Y is selected from halogeno and (1-4C)alkyl;

(ff) a is 0 and Y is halogeno, particularly chloro;

(gg) a is 0 and Y is (1-4C)alkyl, particularly methyl;

(hh) X² is selected from O, S and OC(R⁴)₂ wherein each R⁴ is,independently, hydrogen or (1-4C)alkyl;

(ii) X² is selected from O, S and OCH₂;

(jj) X² is O;

(kk) X² is S;

(ll) X² is OCH₂;

(mm) X² is selected from O, S and OCH₂ and Y is selected from halogenoand (1-4C)alkyl;

(nn) X² is selected from O and OCH₂ and Y is selected from halogeno and(1-4C)alkyl;

(oo) X² is selected from O and OCH₂ and Y is halogeno, particularlychloro;

(pp) X² is selected from O and OCH₂ and Y is (1-4C)alkyl, particularlymethyl;

(qq) X² is OCH₂ and Y is halogeno, particularly chloro;

(rr) X² is OCH₂ and Y is (1-4C)alkyl, particularly methyl;

(ss) X² is O and Y is halogeno, particularly chloro;

(tt) X² is O and Y is (1-4C)alkyl, particularly methyl;

(uu) X² is OCH₂, X is chloro and a is 0;

(vv) X² is OCH₂, Y is methyl and a is 0;

(ww) X² is O, Y is chloro and a is 0;

(xx) X² is O, Y is methyl and a is 0;

(yy) Q² is selected from phenyl and a 5- or 6-membered monocyclicheteroaryl ring, which ring contains 1, 2 or 3 heteroatoms independentlyselected from oxygen, nitrogen and sulfur,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl,mercapto, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵

wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶), whereinR⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl,N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within Q² optionally bears on each saidCH₂ or CH₃ one or more (for example 1, 2, or 3) halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

(zz) Q² is phenyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(aaa) Q² is a 5- or 6-membered monocyclic heteroaryl ring, which ringcontains 1 nitrogen heteroatom and optionally 1 additional heteroatomselected from oxygen, nitrogen and sulfur,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(bbb) Q² is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl,1H-imidazolyl, 1H-pyrazolyl, 1,3-oxazolyl and isoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(ccc) Q² is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl andisoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(ddd) Q² is selected from pyridyl, pyrazinyl, 1,3-thiazolyl andisoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(eee) Q² is selected from 2-,3- or 4-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 3-isoxazolyl,4-isoxazolyl and 5-isoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(fff) Q² is selected from phenyl, 2- or 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 3-isoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(ggg) Q² is selected from 2- or 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 3-isoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(hhh) Q² is selected from 2- or 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl (particularly3-pyridyl, 1,3-thiazol-4-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(iii) Q² is selected from 2-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and 3-isoxazolyl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(yy);

(jjj) Q² is pyrazinyl (particularly 2-pyrazinyl), which optionally bearsone or more substituents (for example 1, 2 or 3), which may be the sameor different, as defined above in (yy);

(kkk) Q² is isoxazolyl (particularly isoxazol-3-yl), which optionallybears one or more substituents (for example 1, 2 or 3), which may be thesame or different, as defined above in (yy);

(lll) Q² is pyridyl (particularly 2-pyridyl or 3-pyridyl, moreparticularly 2-pyridyl), which optionally bears one or more substituents(for example 1, 2 or 3), which may be the same or different, as definedabove in (yy);

(mmm) Q² is 1,3-thiazolyl (particularly 1,3-thiazol-2-yl,1,3-thiazol-4-yl or 1,3-thiazolyl-5-yl), which optionally bears one ormore substituents (for example 1, 2 or 3), which may be the same ordifferent, as defined above in (yy);

(nnn) Q² is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, and isoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

(ooo) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl, and isoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(nnn);

(ppp) Q² is selected from phenyl, 2-pyridyl, 3-pyridyl andisoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(nnn);

(qqq) Q² is selected from 2- or 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl (particularly3-pyridyl, 1,3-thiazol-4-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(nnn);

(rrr) Q² is selected from phenyl; 2-pyridyl, 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from fluoro,chloro, bromo, hydroxy, carboxy, cyano, nitro, amino, methyl, ethyl,isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 2-propynyl,methylthio, methylsulfinyl, methylsulfonyl, acetyl, propionylmethylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino,N-methyl-N-ethylamino methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetoxy, acetamido,fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, hydroxymethyl,2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, cyanomethyl,2-cyanoethyl, carboxymethyl, 2-carboxymethyl, aminomethyl,methylaminomethyl, ethylaminomethyl, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N-methyl-N-ethylaminomethyl, 2-aminoethyl,2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(N,N-dimethylamino)ethyl,2-(N,N-diethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl,carbamoylmethyl, N-methylcarbamoylmethyl andN,N-dimethylcarbamoylmethyl;

(sss) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl, and isoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(rrr);

(ttt) Q² is selected from phenyl, 2-pyridyl, 3-pyridyl andisoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(rrr);

(uuu) Q² is selected from 2- or 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl (particularly3-pyridyl, 1,3-thiazol-4-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(rrr);

(vvv) Q² is selected from 2-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, as defined above in (rrr);

(www) Q² is selected from phenyl, 2-pyridyl, 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy, cyano,nitro, (1-4C)alkyl and (1-4C)alkoxy;

(xxx) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl, and isoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(www);

(yyy) Q² is selected from phenyl, 2-pyridyl, 3-pyridyl andisoxazol-3-yl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(www);

(zzz) Q² is selected from 2- or 3-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 3-isoxazolyl (particularly3-pyridyl, 1,3-thiazol-4-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, as hereinbefore defined in(www);

(aaaa) Q² is phenyl which optionally bears one or more substituents (forexample 1, 2, or 3), which may be the same or different, selected fromfluoro, chloro, bromo, cyano, methyl and methoxy;

(bbbb) Q² is phenyl which bears 1 or 2 substituents, which may be thesame or different, selected from halogeno (particularly fluoro andchloro, more particularly fluoro);

(cccc) Q² is selected from 2-fluorophenyl and 3-fluorophenyl;

(dddd) Q² is 3-fluorophenyl;

(eeee) Q² is 2-fluorophenyl;

(ffff) Q² is selected from 2-pyridyl and 3-pyridyl,

and wherein Q² optionally bears 1 or 2 substituents selected fromfluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

(gggg) Q² is selected from 2-pyridyl and 3-pyridyl,

and wherein Q² bears 1 or 2 substituents selected from hydroxy,(1-4C)alkyl and (1-4C)alkoxy;

(hhhh) Q² is 2-pyridyl which optionally bears 1 or 2 substituentsselected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy(particularly (1-4C)alkyl);

(iiii) Q² is 3-pyridyl which optionally bears 1 or 2 substituentsselected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxyparticularly (1-4C)alkyl);

(jjjj) Q² is selected from 2-pyridyl, 3-pyridyl, 6-methylpyrid-2-yl and6-methylpyrid-3yl;

(kkkk) Q² is 2-pyridyl;

(llll) Q² is 3-pyridyl;

(mmmm) Q² is 6-methylpyrid-2-yl;

(nnnn) Q² is 6-methylpyrid-3yl;

(oooo) Q² is 2-pyrazinyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

(pppp) Q² is 2-pyrazinyl;

(qqqq) Q² is 3-isoxazolyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

(rrrr) Q² is 3-isoxazolyl which bears 1 or 2 substituents, which may bethe same or different, selected from hydroxy, (1-4C)alkyl and(1-4C)alkoxy;

(ssss) Q² is 3-isoxazolyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from (1-4C)alkyl;

(tttt) Q² is selected from 3-isoxazolyl and 5-methyl-3-isoxazolyl;

(uuuu) Q² is 3-isoxazolyl;

(vvvv) Q² is 5-methyl-3-isoxazolyl;

(wwww) Q² is selected from 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and1,3-thiazol-5-yl,

and wherein Q² optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyland (1-4C)alkoxy;

(xxxx) Q² is selected from 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and1,3-thiazol-5-yl;

(yyyy) Q² is 1,3-thiazol-2-yl;

(zzzz) Q² is 1,3-thiazol-4-yl;

(aaaaa) Q² is 1,3-thiazol-5-yl;

(bbbbb) Q² is selected from 2-fluorophenyl, 3-fluorophenyl, 2-pyridyl,3-pyridyl, 6-methylpyrid-2-yl, 6-methylpyrid-3-yl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and5-methyl-3-isoxazolyl;

(ccccc) Q² is selected from 2-pyridyl, 3-pyridyl, 6-methylpyrid-2-yl,6-methylpyrid-3-yl, 2-pyrazinyl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and 5-methyl-3-isoxazolyl;

(ddddd) Q² is selected from 2-pyridyl, 6-methylpyrid-3-yl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 5-methyl-3-isoxazolyl(particularly 6-methylpyrid-3-yl, 1,3-thiazol-4-yl and5-methyl-3-isoxazolyl);

(eeeee) Q² is selected from 2-fluorophenyl, 3-fluorophenyl, 2-pyridyl,6-methylpyrid-2-yl, 6-methylpyrid-3-yl, 2-pyrazinyl, 1,3-thiazol-4-yland 5-methyl-3-isoxazolyl (particularly 2-fluorophenyl, 3-fluorophenyl,2-pyridyl, 6-methylpyrid-3-yl, 2-pyrazinyl and 1,3-thiazol-4-yl);

(fffff) Q² is selected from 2-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and 5-methyl-3-isoxazolyl;

(ggggg) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy, cyano,nitro, amino, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylamino andN,N-di-[(1-4C)alkyl]amino,

and X² is OCH₂;

(hhhhh) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy, cyano,nitro, amino, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylamino andN,N-di-[(1-4C)alkyl]amino,

X² is OCH₂,

and Y is selected from halogeno (particularly chloro) and (1-4C)alkyl(particularly methyl);

(iiiii) Q² is selected from 2-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy, cyano,nitro, amino, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylamino andN,N-di-[(1-4C)alkyl]amino,

and X² is OCH₂;

(jjjjj) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy,(1-4C)alkyl and (1-4C)alkoxy,

and X² is OCH₂;

(kkkkk) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy,(1-4C)alkyl and (1-4C)alkoxy,

X² is OCH₂,

and Y is selected from chloro and methyl;

(lllll) Q² is selected from phenyl, 2-pyridyl, 2-pyrazinyl,1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy, cyano,nitro, amino, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylamino andN,N-di-[(1-4C)alkyl]amino,

X² is OCH₂,

and a is 0;

(mmmmm) Q² is selected from 2-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and isoxazol-3-yl,

and wherein Q² optionally bears 1, 2, or 3 substituents, which may bethe same or different, selected from fluoro, chloro, hydroxy, cyano,nitro, amino, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylamino andN,N-di-[(1-4C)alkyl]amino,

X² is OCH₂,

and a is 0;

(nnnnn) Q² is 3-pyridyl which optionally bears 1, 2, or 3 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, cyano, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylamino and N,N-di-[(1-4C)alkyl]amino,

and X² is O;

(ooooo) Q² is 3-pyridyl which optionally bears 1, 2, or 3 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, cyano, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylamino and N,N-di-[(1-4C)alkyl]amino,

X² is O,

and Y is selected from halogeno particularly chloro) and (1-4C)alkyl(particularly methyl);

(ppppp) Q² is 3-pyridyl which optionally bears 1 or 2 (particularly 1)(1-4C)alkyl substituents,

and X² is O;

(qqqqq) Q² is 3-pyridyl which optionally bears 1 or 2 (particularly 1)(1-4C)alkyl substituents,

X² is O,

and Y is selected from chloro and methyl;

(rrrrr) Q² is 3-pyridyl which optionally bears 1 or 2 (particularly 1)(1-4C)alkyl substituents,

X² is O,

and a is 0;

(sssss) Q² is selected from 3-pyridyl and 6-methylpyrid-3-yl,

X² is O,

and Y is selected from chloro and methyl;

(ttttt) Q² is selected from 3-pyridyl and 6-methylpyrid-3-yl,

X² is O,

and a is 0;

(uuuuu) Q² is selected from 2-pyridyl and 3-pyridyl (particularly2-pyridyl),

and wherein Q² optionally bears a (1-4C)alkyl substituent (for examplemethyl),

X² is O,

a is 0, and

Y is (1-4C)alkyl (for example methyl);

(vvvvv) The group —X²-Q² is selected from pyrid-2-ylmethoxy,1,3-thiazol-4-ylmethoxy, (5-methylisoxazol-3-yl)methoxy,1,3-thiazol-5-ylmethoxy, pyrazin-2-ylmethoxy,(6-methylpyrid-2-yl)methoxy, (2-fluorobenzyl)oxy, (3-fluorobenzyl)oxy,(6-methylpyrid-3-yl)oxy, 1,3-thiazol-2-ylmethoxy and pyrid-3-yloxy;

(wwwww) X¹ is selected from a direct bond and C(R⁷)₂, wherein each R⁷,which may be the same or different, is selected from hydrogen andmethyl;

(xxxxx) X¹ is selected from a direct bond, CH₂ and CH(CH₃);

(yyyyy) X¹ is selected from a direct bond and CH₂;

(zzzzz) X¹ is C(R⁷)₂, wherein each R⁷, which may be the same ordifferent, is selected from hydrogen and (1-4C)alkyl (particularly(1-2C)alkyl, for example methyl);

(aaaaaa) X¹ is CH₂;

(bbbbbb) X¹ is CH(CH₃);

(cccccc) X¹ is a direct bond;

(dddddd) Q¹ is a 5 or 6 membered saturated heterocyclyl group containing1 nitrogen heteroatom and optionally 1 or 2 (for example 1) additionalheteroatoms independently selected from oxygen, nitrogen and sulfur, andwhich ring is linked to the group X¹ by a ring carbon;

(eeeeee) Q¹ is a 5 or 6 membered saturated heterocyclyl group containing1 nitrogen heteroatom and optionally 1 additional heteroatomindependently selected from oxygen and nitrogen, and which ring islinked to the group X¹ by a ring carbon;

(ffffff) Q¹ is selected from azetidinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected fromhalogeno, trifluoromethyl, hydroxy, carbamoyl, (1-4C)alkyl,(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(gggggg) Q¹ is selected from pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different; selected fromhalogeno, trifluoromethyl, hydroxy, carbamoyl, (1-4C)alkyl,(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(hhhhhh) Q¹ is selected from pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(iiiiii) Q¹ is selected from azetidin-2-yl, azetidin-3-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-2-yl, morpholin-3-yl,thiomorpholin-2-yl, thiomorpholin-3-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-2-yl, 2-, 3- or 4-homopiperidinyl, 2, 3, 5, 6or 7-homopiperazinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(jjjjjj) Q¹ is piperidinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein the piperidinyl group within Q¹ optionally bears an oxosubstituent;

(kkkkkk) Q¹ is pyrrolidinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein the pyrrolidinyl group within Q¹ optionally bears an oxosubstituent;

(llllll) Q¹ is morpholinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein the morpholinyl group within Q¹ optionally bears an oxosubstituent;

(mmmmmm) Q¹ is piperazinyl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein the piperazinyl group within Q¹ optionally bears an oxosubstituent;

(nnnnnn) Q¹ is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,morpholin-2-yl, morpholin-3-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-2-yl and piperazin-3-yl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(oooooo) Q¹ is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,morpholin-2-yl, morpholin-3-yl, piperidin-2-yl, piperidin-3-yl andpiperazin-2-yl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(pppppp) Q¹ is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,morpholin-3-yl, piperidin-2-yl and piperidin-3-yl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(qqqqqq) Q¹ is selected from pyrrolidin-2-yl and piperidin-2-yl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent;

(rrrrrr) Q¹ is pyrrolidin-2-yl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy;

(ssssss) Q¹ is piperidin-2-yl,

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy;

(tttttt) Q¹ is pyrrolidin-2-yl;

(uuuuuu) Q¹ is pyrrolidin-3-yl;

(vvvvvv) Q¹ is piperidin-2-yl;

(wwwwww) Q¹ is piperidin-3-yl;

(xxxxxx) Q¹ is piperidin-4-yl;

(yyyyyy) Q¹ is morpholin-3-yl;

(zzzzzz) Q¹ is morpholin-2-yl;

(aaaaaaa) Q¹ is 1-methylpiperazin-2-yl;

(bbbbbbb) Q¹ is 1-methylpiperazin-3-yl;

(ccccccc) Q¹ is selected from azetidinyl, pyrolidinyl, piperidinyl,homopiperidinyl, piperazinyl, morpholinyl and thiomorpholinyl(particularly pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl),

and wherein Q¹ is linked to the group X¹—O by a ring carbon atom,

and wherein Q¹ optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected fromhalogeno, trifluoromethyl, hydroxy, carbamoyl, (1-4C)alkyl,(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,

and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent,

and X¹ is selected from a direct bond, CH₂ and CH(CH₃);

(ddddddd) Q¹-X¹ is selected from pyrrolidin-2-ylmethyl,pyrrolidin-3-ylmethyl, morpholin-2-ylmethyl, morpholin-3-ylmethyl,piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl andpiperazin-2-ylmethyl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy;

(eeeeeee) Q¹-X¹ is selected from pyrrolidin-2-ylmethyl,morpholin-3-ylmethyl and piperidin-2-ylmethyl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy;

(fffffff) Q¹-X¹ is selected from (2R)-pyrrolidin-2-ylmethyl,(2S)-pyrrolidin-2-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,(3S)-pyrrolidin-3-ylmethyl, (2R)-piperidin-2-ylmethyl,(2S)-piperidin-2-ylmethyl, (3R)-piperidin-3-ylmethyl,(3S)-piperidin-3-ylmethyl, (2R)-piperazin-2-ylmethyl,(2S)-piperazin-2-ylmethyl, (3R)-piperazin-3-ylmethyl,(3S)-piperazin-3-ylmethyl, (2R)-morpholin-2-ylmethyl,(2S)-morpholin-2-ylmethyl, (3R)-morpholin-3-ylmethyl and(3S)-morpholin-3-ylmethyl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from halogeno, hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy (particularly hydroxy, methyl and methoxy);

(ggggggg) Q¹-X¹ is selected from (2R)-pyrrolidin-2-ylmethyl,(2S)-pyrrolidin-2-ylmethyl, (3R)-morpholin-3-ylmethyl and(3S)-morpholin-3-ylmethyl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from halogeno, hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy (particularly hydroxy, methyl and methoxy);

(hhhhhhh) Q¹-X¹ is selected from (3R)-pyrrolidin-3-ylmethyl and(3S)-pyrrolidin-3-ylmethyl,

and wherein the pyrrolidinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, oxo, (1-3C)alkyl and (1-3C)alkoxy;

(iiiiiii) Q¹-X¹ is selected from (2R)-pyrrolidin-2-ylmethyl and(2S)-pyrrolidin-2-ylmethyl,

and wherein the pyrrolidinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, oxo, (1-3C)alkyl and (1-3C)alkoxy;

(jjjjjjj) Q¹-X¹ is selected from (3R)-morpholin-3-ylmethyl and(3S)-morpholin-3-ylmethyl,

and wherein the morpholinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, (1-3C)alkyl and (1-3C)alkoxy;

(kkkkkkk) Q¹-X¹ is selected from (2R)-morpholin-2-ylmethyl and(2S)-morpholin-2-ylmethyl,

and wherein the morpholinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, (1-3C)alkyl and (1-3C)alkoxy;

(lllllll) Q¹-X¹ is selected from (2R)-piperidin-2-ylmethyl and(2S)-piperidin-2-ylmethyl,

and wherein the piperidinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, oxo, (1-3C)alkyl and (1-3C)alkoxy,

(mmmmmmm) Q¹-X¹ is selected from (3R)-piperidin-3-ylmethyl and(3S)-piperidin-3-ylmethyl,

and wherein the piperidinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, oxo, (1-3C)alkyl and (1-3C)alkoxy;

(nnnnnnn) Q¹-X¹ is piperidin-4-ylmethyl, and wherein the piperidinylgroup optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, hydroxy, oxo, (1-3C)alkyl and(1-3C)alkoxy;

(ooooooo) Q¹-X¹ is selected from (2R)-piperazin-2-ylmethyl and(2S)-piperazin-2-ylmethyl,

and wherein the piperazinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, oxo, (1-3C)alkyl and (1-3C)alkoxy;

(ppppppp) Q¹-X¹ is selected from (3R)-piperazin-3-ylmethyl and(3S)-piperazin-3-ylmethyl,

and wherein the piperazinyl group optionally bears 1 or 2 substituents,which may be the same or different, selected from fluoro, chloro,hydroxy, oxo, (1-3C)alkyl and (1-3C)alkoxy;

(qqqqqqq) Q¹-X¹ is selected from (3R)-pyrrolidin-3-yl and(3S)-pyrrolidin-3-yl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from halogeno, hydroxy, oxo, (1-4C)alkyl and(1-4C)alkoxy (particularly hydroxy, methyl and methoxy);

For the avoidance of any doubt, the rings represented by Q¹ described in(dddddd) to (qqqqqqq) above are all substituted on the ring nitrogen bythe group Z-X³—C(O) in accordance with Formula I;

(rrrrrrr) X³ is selected from a group of the formula-(Q³)_(m)-(CR¹⁰R¹¹)_(q)— and a group of the formula—(CR⁸R⁹)_(q)-(Q³)_(m)-, wherein m is 0 or 1, q is 1, 2, 3 or 4, and Q³,R⁸, R⁹, R¹⁰ and R¹¹ are as hereinbefore defined;

(sssssss) X³ is a group of the formula -Q³-, for example(3-7C)cycloalkylene such as cyclopropylidene;

(ttttttt) X³ is selected from cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, methylene-(3-6C)cycloalkylene,(3-6C)cycloalkylene-methylene-, ethylene-(3-6C)cycloalkylene and(3-6C)cycloalkylene-ethylene-,

and wherein any CH₂ or CH₃ group within an X³ group, optionally bears oneach said CH₂ or CH₃ group one or more (for example 1 or 2) halogenosubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X³ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-6C)alkoxy;

(uuuuuuu) X³ is a group of the formula —(CR⁸R⁹)_(q)—,

q is 1, 2, 3 or 4 (particularly 1 or 2),

each of R⁸ and R⁹, which may be the same or different, is selected fromhydrogen and (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within an X³ group, optionally bears oneach said CH₂ or CH₃ group one or more (for example 1 or 2) halogenosubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X³ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-6C)alkoxy;

(vvvvvvv) X³ is a group of the formula —(CR⁸R⁹)_(q)—,

q is 1, 2, 3 or 4 (particularly 1 or 2),

each of R⁸ and R⁹, which may be the same or different, is selected fromhydrogen and (1-6C)alkyl, provided that at least one R⁸ or R⁹ group inX³ is (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within an X³ group, optionally bears oneach said CH₂ or CH₃ group one or more (for example 1 or 2) halogenosubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X³ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-6C)alkoxy;

(wwwwwww) X³ is selected from a group of the formula —(CR⁸R⁹)—,—(CR⁸R⁹CH₂)—, —(CR⁸R⁹CH₂CH₂)—, —(CH₂CR⁸R⁹)— and —(CH₂CH₂CR⁸R⁹)—,

each of R⁸ and R⁹, which may be the same or different, is selected fromhydrogen and (1-6C)alkyl, provided that at least one R⁸ or R⁹ group inX³ is (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within an X³ group, optionally bears oneach said CH₂ or CH₃ group one or more (for example 1 or 2) halogenosubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X³ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-6C)alkoxy;

(xxxxxxx) X³ is selected from a group of the formula —(CR⁸R⁹)—,—(CR⁸R⁹CH₂)—, —(CR⁸R⁹CH₂CH₂)—, —(CH₂CR⁸R⁹)— and —(CH₂CH₂CR⁸R⁹)—,

each of R⁸ and R⁹, which may be the same or different, is selected fromhydrogen and (1-6C)alkyl, provided that at least one R⁸ or R⁹ group inX³ is a branched (1-6C)alkyl group,

and wherein any CH₂ or CH₃ group within an X³ group, optionally bears oneach said CH₂ or CH₃ group one or more (for example 1 or 2) halogenosubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X³ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-6C)alkoxy;

(yyyyyyy) X³ is selected from a group of the formula —(CR⁸R⁹)—,—(CR⁸R⁹CH₂)—, —(CR⁸R⁹CH₂CH₂)—, —(CH₂CR⁸R⁹)— and —(CH₂CH₂CR⁸R⁹)—,

each of R⁸ and R⁹, which may be the same or different, is selected fromhydrogen and (1-6C)alkyl, provided that at least one R⁸ or R⁹ group inX³ is a branched alkyl group selected from iso-propyl, iso-butyl,sec-butyl and tert-butyl,

and wherein any CH₂ or CH₃ group within an X³ group, optionally bears oneach said CH₂ or CH₃ group one or more (for example 1 or 2) halogenosubstituents,

and wherein any CH₂ group which is attached to 2 carbon atoms or any CH₃group which is attached to a carbon atom within a X³ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy and (1-6C)alkoxy;

(zzzzzzz) X³ is selected from a group of the formula —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —(CR⁸R⁹)—, —(CR⁸R⁹CH₂)— and —(CH₂CR⁸R⁹)—,

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen;

(aaaaaaaa) X³ is selected from a group of the formula —CH₂—, —CH₂CH₂—,—(CHR⁸)—, —(CHR⁸CH₂)— and —(CH₂CHR⁸)—,

wherein R⁸ is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl,and (1-3C)alkoxy-(1-4C)alkyl;

(bbbbbbbb) X³ is selected from a group of the formula —(CH₂)_(q)—,wherein q is 1, 2 or 3, (particularly q is 1 or 2);

(cccccccc) X³ is selected from —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)— andcyclopropylidene (particularly —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂C(CH₃)₂—and cyclopropylidene);

(dddddddd) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylaminoand a group of the formula:Q⁴-X⁵—

wherein X⁵ is a direct bond or is selected from O, N(R¹²), SO₂ andSO₂N(R¹²), wherein R¹² is hydrogen or (1-6C)alkyl, and Q⁴ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁵ is a direct bond, Q⁴ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is a fully saturated 4, 5, 6 or7-membered monocyclic heterocyclyl group containing 1 or 2 heteroatomsselected from oxygen, nitrogen and sulfur,

and wherein any CH₂ or CH₃ group within a Z group, other than a CH₂group within a heterocyclyl ring, optionally bears on each said CH₂ orCH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group within a Z substituent optionallybears 1 or 2 oxo substituents;

(eeeeeeee) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula:Q⁴-X⁵—

wherein X⁵ is a direct bond or is selected from O and N(R¹²), whereinR¹² is hydrogen or (1-6C)alkyl, and Q⁴ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁵ is a direct bond, Q⁴ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is a non-aromatic fullysaturated or partially saturated 4, 5, 6 or 7-membered monocyclicheterocyclyl group containing 1 heteroatom selected from oxygen andnitrogen and optionally a further heteroatom selected from oxygen,nitrogen and sulfur,

and wherein any CH₂ or CH₃ group within a Z group, other than a CH₂group within a heterocyclyl ring, optionally bears on each said CH₂ orCH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group within a Z substituent optionallybears 1 or 2 oxo substituents;

(ffffffff) Z is selected from hydroxy, amino, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula:Q⁴-X⁵—

wherein X⁵ is a direct bond or is selected from O and N(R¹²), whereinR¹² is hydrogen or (1-6C)alkyl, and Q⁴ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

provided that when X⁵ is a direct bond, Q⁴ is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, whichheterocyclyl group may be carbon or nitrogen linked to the group towhich it is attached,

and wherein any CH₂ or CH₃ group within a Z group, other than a CH₂group within a heterocyclyl ring, optionally bears on each said CH₂ orCH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group within a Z substituent optionallybears 1 or 2 oxo substituents;

(gggggggg) Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyland a group of the formula:Q⁴-X⁵—

wherein X⁵ is selected from O and N(R¹²), wherein R¹² is hydrogen or(1-4C)alkyl, and Q⁴ is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, whichheterocyclyl group may be carbon or nitrogen linked to the group towhich it is attached,

and wherein any CH₂ or CH₃ group within a Z group, other than a CH₂group within a heterocyclyl ring, optionally bears on each said CH₂ orCH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group within a Z substituent optionallybears 1 oxo substituent;

(hhhhhhhh) Z is selected from amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,homopiperidin-1-yl and homopiperazin-1-yl,

and wherein any CH₂ or CH₃ group within a Z group, optionally bears oneach said CH₂ or CH₃ group one or more fluoro substituents or asubstituent selected from hydroxy, cyano, amino, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, cyano, hydroxy, amino,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino,

and wherein any heterocyclyl group within a Z substituent optionallybears 1 oxo substituent;

(iiiiiiii) Z is selected from hydroxy, (1-6C)alkoxy,hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyland a group of the formula:Q⁴-X⁵—

wherein X⁵ is O, and Q⁴ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein any heterocyclyl group in Z is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl andoxepanyl,

and wherein any CH₂ or CH₃ group within a Z group, optionally bears oneach said CH₂ or CH₃ group one or more fluoro substituents or asubstituent selected from hydroxy, cyano, amino, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents, which may be thesame or different, selected from halogeno, cyano, hydroxy, amino,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

(jjjjjjjj) Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy;

(kkkkkkkk) Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy,2-methoxyethoxy, amino, methylamino, ethylamino,N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino,N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino,N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino,N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,tetrahydrofuranyl and tetrahydropyranyl,

and wherein any heterocyclyl group within Z optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

(llllllll) Z is selected from N-[hydroxy-(2-4C)alkyl]-amino,N-[(1-4C)alkoxy-(2-4C)alkyl]-amino,N-[hydroxy-(2-4C)alkyl]-N-[(1-4C)alkyl]amino,N,N-di-[hydroxy-(2-4C)alkyl]-amino,N-[(1-4C)alkoxy-2-4C)alkyl]-N-[(1-4C)alkyl]amino andhydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy;

(mmmmmmmm) Z is selected from pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, homopiperidine-1-yl, homopiperazin-1-yl,(particularly Z is selected from pyrrolidin-1-yl, piperidino,piperazin-1-yl and morpholino),

and wherein the heterocyclyl group within Z optionally bears one or more(for example 1, 2 or 3) substituents, which may be the same ordifferent, selected from fluoro, chloro, cyano, hydroxy, amino,carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, acetyl, propionyl, 2-fluoroethyl,2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyacetyl, aminoacetyl,methylaminoacetyl, ethylaminoacetyl, dimethylaminoacetyl andN-methyl-N-ethylaminoacetyl,

and wherein the heterocyclyl group within Z optionally bears an oxosubstituent;

(nnnnnnnn) Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy,2-methoxyethoxy, amino, methylamino, ethylamino, dimethylamino,N-methyl-N-ethylamino, di-ethylamino, pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl;

(oooooooo) Z is selected from hydroxy, methoxy, ethoxy, dimethylaminoand pyrrolidin-1-yl;

(pppppppp) Z is hydroxy;

(qqqqqqqq) Z is (1-6C)alkoxy (particularly methoxy or ethoxy);

(rrrrrrrr) Z is di-[(1-6C)alkyl]amino (particularly dimethylamino);

(ssssssss) Z is Q⁴-X⁵—, wherein X⁵ is a direct bond and Q⁴ isheterocyclyl (particularly pyrrolidin-1-yl);

(tttttttt) Z is as defined in any of (dddddddd) to (ssssssss) above,

and wherein X³ is selected from —CH₂—, —CH₂CH₂—, —(CR⁸R⁹)—,—(CR⁸R⁹CH₂)—, —(CH₂CR⁸R⁹)— and (3-6C)cycloalkenylene (for examplecyclopropylene such as 1,1-cyclopropylene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen;

(uuuuuuuu) Z-X³ is selected from hydroxymethyl, dimethylaminomethyl,2-hydroxyprop-2-yl, 1-hydroxycyclopropyl, 2-hydroxy-1,1-dimethylethyl,2-hydroxyeth-2-yl, ethoxymethyl, methoxymethyl andpyrrolidin-1-ylmethyl;

(vvvvvvvv) Z-X³ is hydroxymethyl;

(wwwwwwww) Z-X³— is selected from tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl,piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, whichheterocyclyl is linked to the carbonyl group in Formula I, by a ringcarbon,

and wherein the heterocyclyl group within Z-X³ optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, hydroxy, oxo, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; and

(xxxxxxxx) Z-X³— is selected from tetrahydrofuranyl, 1,3-dioxolanyl,tetrahydropyranyl, 1,4-dioxanyl, oxepanyl (for example Z-X³ is selectedtetrahydrofuran-2-yl or tetrahydropyran-2-yl).

An embodiment of the present invention is a quinazoline derivative ofthe formula I wherein R¹, R², Q¹, Q², X¹, X², X³, Y, a and Z have any ofthe values defined hereinbefore with the proviso that m, p and q are notall 0, and

when m is 0 and the sum of p and q is 6, then Z is not the group Q⁴-X⁵—wherein X⁵ is a direct bond and Q⁴ is heterocyclyl, and

when m is 0 and the sum of p and q is 1, 2, 3, 4 or 5, then Z is notamino, (1-6C)alkylamino or di-[(1-6C)alkyl]amino or the group Q⁴-X⁵—wherein X⁵ is a direct bond and Q⁴ is heterocyclyl,

or a pharmaceutically acceptable salt thereof.

In particular, in this embodiment, the group Z-X³— is notdimethylaminomethyl or pyrrolidin-1-ylmethyl.

Another embodiment of the present invention is a quinazoline derivativeof the formula I wherein R¹, R², Q¹, Q², X¹, X², Y and a have any of thevalues defined hereinbefore, X³ is a group of the formula:—(CR⁸R⁹)_(p)-(Q³)_(m)-(CR¹⁰R¹¹)_(q)—

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4,

each of R⁸, R⁹, R¹⁰ and R¹¹, which may be the same or different, isselected from hydrogen and (1-6C)alkyl, and

Q³ is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene;

Z is selected from hydroxy, (1-6C)alkoxy, (1-6C)alkylsulfonyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:Q⁴-X⁵—

wherein X⁵ is selected from O, N(R¹²), SO₂ and SO₂N(R¹²), wherein R¹² ishydrogen or (1-6C)alkyl, and Q⁴ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Zsubstituent are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹³), CO, —C═C— and —C≡C— whereinR¹³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within any Z or X³ group, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionallybears one or more (for example 1, 2 or 3) substituents which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group within a Z substituent optionallybears 1 or 2 oxo or thioxo substituents,

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a quinazoline derivativeof the formula I wherein:

R¹ is selected from hydrogen and (1-3C)alkoxy, (for example R¹ ishydrogen or methoxy, particularly hydrogen);

X¹ is selected from a direct bond, CH₂ or CH(CH₃);

X² is selected from O, S and OCH₂;

Q² is aryl or heteroaryl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl,mercapto, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵

wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶), whereinR⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl,N,N-di-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within Q² optionally bears on each saidCH₂ or CH₃ one or more (for example 1, 2, or 3) halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

and wherein R², Y, Q¹, X³, a and Z have any of the values definedhereinbefore;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for Q² is phenyl or a 5 or 6membered heteroaryl ring containing 1 nitrogen heteroatom and optionally1 additional heteroatom selected from O, S and N, and wherein Q²optionally bears one or more substituents as defined above.

In this embodiment a particular value for X² is O or OCH₂.

In this embodiment a particular value for a is 0 or 1, more particularly0.

In this embodiment, a particular value for Y is halogeno (such as chloroor fluoro, particularly chloro) or (1-4C)alkyl (such as methyl).

A particular embodiment of the present invention is a quinazolinederivative of the formula I wherein:

R¹ is selected from hydrogen and (1-3C)alkoxy, (for example R¹ ishydrogen or methoxy, particularly hydrogen);

X¹ is a direct bond or CH₂;

X² is selected from O, S and OCH₂;

Q² is heteroaryl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl,mercapto, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵

wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶), whereinR⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl,N,N-di-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within Q² optionally bears on each saidCH₂ or CH₃ one or more (for example 1, 2, or 3) halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1,4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

and wherein R², Y, Q¹, X³, a and Z have any of the values definedhereinbefore;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for Q² is a 5 or 6 memberedheteroaryl ring containing 1 nitrogen heteroatom and optionally 1additional heteroatom selected from O, S and N, and wherein Q²optionally bears one or more substituents as defined above.

In this embodiment a particular value for X² is OCH₂.

In this embodiment a particular value for a is 0 or 1, more particularly0.

Another embodiment of the present invention is a quinazoline derivativeof the formula I wherein:

R¹ is selected from hydrogen and (1-3C)alkoxy, (for example R¹ ishydrogen or methoxy, particularly hydrogen);

Y is selected from halogeno, (1-4C)alkyl, (2-4C)alkenyl and(2-4C)alkynyl;

a is 0 or 1;

R² is halogeno;

X² is selected from O, S and OCH₂;

Q² is phenyl or a 5 or 6 membered heteroaryl ring containing 1 nitrogenheteroatom and optionally 1 additional heteroatom selected from O, S andN,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

X¹ is a direct bond, CH₂ or CH(CH₃);

Q¹ is selected from pyrrolidinyl, morpholinyl, piperazinyl andpiperidinyl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy,

and wherein Q¹ optionally bears an oxo substituent,

and wherein Q¹ is linked to the group X¹ by a ring carbon;

X³ is selected from —CH₂—, —CH₂CH₂—, —(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—,—(CH₂CR⁸R⁹)— and (3-6C)cycloalkylene (for example cyclopropylene such ascyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen;

Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X¹ is CH₂ and Q¹ is selectedfrom pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-2-yl, morpholin-3-yl,piperidin-2-yl, piperidinyl-3-yl, piperidinyl, piperazin-2-yl andpiperazin-3yl, and wherein Q¹ optionally bears one or more substituentsas defined above. Still more particularly in this embodiment X¹ is CH₂and Q¹ is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,morpholin-2-yl, morpholin-3-yl, piperidin-2-yl, piperidinyl-3-yl,piperidin-4-yl, piperazin-2-yl and piperazin-3yl, and wherein Q¹optionally bears one or more substituents as defined above, and Z-X³ ishydroxymethyl.

In this embodiment another particular value for X¹ is a direct bond andQ¹ is selected from pyrrolidin-3-yl and piperidin-3-yl.

In this embodiment a particular value for Q² is phenyl, pyridyl,pyrazinyl, 1,3-thiazolyl or isoxazolyl, more particularly Q² is selectedfrom 2-pyridyl, 3-pyridyl, 2-pyrazinyl, 1,3-thiazol-2-yl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 3-isoxazolyl,

and wherein Q² optionally bears one or more substituents as definedabove.

Another embodiment of the present invention is a quinazoline derivativeof the formula I wherein:

R¹ is selected from hydrogen and (1-3C)alkoxy, (for example R¹ ishydrogen or methoxy, particularly hydrogen);

Y is selected from halogeno, (1-4C)alkyl, (2-4C)alkenyl and(2-4C)alkynyl;

a is 0 or 1;

R² is halogeno;

X² is selected from O, S and OCH₂;

Q² is a 5 or 6 membered heteroaryl ring containing 1 nitrogen heteroatomand optionally 1 additional heteroatom selected from O, S and N,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl;

X¹ is a direct bond or CH₂;

Q¹ is selected from pyrrolidinyl, morpholinyl and piperidinyl,

and wherein Q¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy,

and wherein Q¹ optionally bears an oxo substituent,

and wherein Q¹ is linked to the group X¹ by a ring carbon;

X³ is selected from —CH₂—, —CH₂CH₂—, —(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—,—(CH₂CR⁸R⁹)— and (3-6C)cycloalkylene (for example cyclopropylene such ascyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen;

Z is selected from hydroxy, amino, (1-6C)alkylamino,hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino,di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X¹ is CH₂ and Q¹ is selectedfrom pyrrolidin-2-yl, morpholin-3-yl and piperidin-2-yl. Still moreparticularly in this embodiment X¹ is CH₂ and Q¹ is selected frompyrrolidin-2-yl, morpholin-3-yl and piperidin-2-yl and Z-X³ ishydroxymethyl.

In this embodiment a particular value for Q² is pyridyl, pyrazinyl,1,3-thiazolyl or isoxazolyl, more particularly Q² is selected from2-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and3-isoxazolyl,

and wherein Q² optionally bears one or more substituents as definedabove.

Another embodiment of the compounds of Formula I is a quinazolinederivative of the Formula Ia:

wherein:

R² is selected from hydrogen and halogeno;

Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyland (2-4C)alkynyl (particularly Y is halogeno or methyl, moreparticularly Y is chloro);

Q² is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl andisoxazolyl (more particularly Q² is selected from phenyl, 2-pyridyl,2-pyrazinyl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; and

Z and X³ are as hereinbefore defined in relation to Formula I;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X³ is —CH₂—, —CH₂CH₂—,—(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—, —(CH₂CR⁸R⁹)— or (3-6C)cycloalkylene (forexample cyclopropylene such as cyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen(particularly, R⁸ and R⁹ are selected from hydrogen and methyl).

A particular value for Z in this embodiment is hydroxy, amino,(1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy or (1-4C)alkoxy-(2-6C)alkoxy. Moreparticularly in this embodiment Z is hydroxy, di-[(1-3C)alkyl]amino (forexample dimethylamino) or (1-6C)alkoxy (for example methoxy or ethoxy),still more particularly Z is hydroxy.

Another embodiment of the compounds of the Formula I is a quinazolinederivative of the Formula Ia wherein:

R² is selected from hydrogen and halogeno;

-   Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy,    (2-4C)alkenyl and (2-4C)alkynyl (particularly Y is halogeno or    methyl, more particularly Y is chloro);

Q² is selected from pyridyl, pyrazinyl, 1,3-thiazolyl and isoxazolyl(more particularly Q² is selected from 2-pyridyl, 2-pyrazinyl,1,3-thiazolyl, 1,3-thiazol-5-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; and

Z and X³ are as hereinbefore defined in relation to Formula I;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X³ is from —CH₂—, —CH₂CH₂—,—(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—, —(CH₂CR⁸R⁹)— or (3-6C)cycloalkylene (forexample cyclopropylene such as cyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen(particularly, R⁸ and R⁹ are selected from hydrogen and methyl).

A particular value for Z in this embodiment is hydroxy, amino,(1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy or (1-4C)alkoxy-(2-6C)alkoxy. Moreparticularly in this embodiment Z is hydroxy or di-[(1-3C)alkyl]amino(for example methylamino), still more particularly Z is hydroxy.

In this embodiment a further particular value for X³ is —CH₂— orCH₂CH₂—, and Z is hydroxy or di-[(1-3C)alkyl]amino (particularly Z-X³ ishydroxymethyl).

A further particular embodiment of the compounds of Formula I is aquinazoline derivative of the Formula Ib:

wherein:

R² is selected from hydrogen and halogeno (particularly hydrogen);

Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyland (2-4C)alkynyl (particularly Y is halogeno, such as chloro);

Q² is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl andisoxazolyl (more particularly Q² is selected from phenyl, 2-pyridyl,3-pyridyl, 2-pyrazinyl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl and3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; and

Z and X³ are as hereinbefore defined in relation to Formula I;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X³ is —CH₂—, —CH₂CH₂—,—(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—, —(CH₂CR⁸R⁹)— or (3-6C)cycloalkylene (forexample cyclopropylene such as cyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen(particularly, R⁸ and R⁹ are selected from hydrogen and methyl). Moreparticularly, in this embodiment X³ is —CH₂—.

A particular value for Z in this embodiment is hydroxy, amino,(1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy or (1-4C)alkoxy-(2-6C)alkoxy. Moreparticularly in this embodiment Z is hydroxy or di-[(1-3C)alkyl]amino(for example dimethylamino), still more particularly Z is hydroxy.

In this embodiment a further particular value for X³ is —CH₂— or—CH₂CH₂—, and Z is hydroxy or di-[(1-3C)alkyl]amino (particularly Z-X³is hydroxymethyl).

A further particular embodiment of the compounds of Formula I is aquinazoline derivative of the Formula Ib wherein:

R² is selected from hydrogen and halogeno (particularly hydrogen);

Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyland (2-4C)alkynyl (particularly Y is halogeno or methyl, moreparticularly Y is chloro);

Q² is selected from pyridyl, pyrazinyl, 1,3-thiazolyl and isoxazolyl(more particularly Q² is selected from 2-pyridyl, 2-pyrazinyl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 3-isoxazolyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; and

Z and X³ are as hereinbefore defined in relation to Formula I;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X³ is —CH₂—, —CH₂CH₂—,—(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—, —(CH₂CR⁸R⁹)— or (3-6C)cycloalkylene (forexample cyclopropylene such as cyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen(particularly, R⁸ and R⁹ are selected from hydrogen and methyl).

A particular value for Z in this embodiment is hydroxy, amino,(1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy or (1-4C)alkoxy-(2-6C)alkoxy. Moreparticularly in this embodiment Z is hydroxy or di-[(1-3C)alkyl]amino(for example dimethylamino), still more particularly Z is hydroxy.

In this embodiment a further particular value for X³ is —CH₂— or—CH₂CH₂—, and Z is hydroxy or di-[(1-3C)alkyl]amino (particularly Z-X³is hydroxymethyl).

Another embodiment of the compounds of Formula I is a quinazolinederivative of the Formula Ic:

wherein:

R² is selected from hydrogen and halogeno;

Y is selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyland (2-4C)alkynyl (particularly Y is halogeno or methyl);

Q² is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl andisoxazolyl (more particularly Q² is 3-pyridyl),

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,hydroxy, cyano, carboxy, nitro, amino, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,(1-4C)alkylsulfonyl, (2-4C)alkanoyl, N-(1-4C)alkylamino,N,N-di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; and

Z and X³ are as hereinbefore defined in relation to Formula I;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for X³ is from —CH₂—, —CH₂CH₂—,—(CR⁸R⁹)—, —(CR⁸R⁹CH₂)—, —(CH₂CR⁸R⁹)— or (3-6C)cycloalkylene (forexample cyclopropylene such as cyclopropylidene),

wherein each of R⁸ and R⁹, which may be the same or different, isselected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl, provided that R⁸ and R⁹ are not both hydrogen(particularly, R⁸ and R⁹ are selected from hydrogen and methyl). Moreparticularly, in this embodiment X³ is —CH₂—.

A particular value for Z in this embodiment is hydroxy, amino,(1-6C)alkylamino, hydroxy-(2-6C)alkylamino,(1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino,N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino,di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino,N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino,(1-6C)alkoxy, hydroxy-(2-6C)alkoxy or (1-4C)alkoxy-(2-6C)alkoxy, orheterocyclyl.

More particularly in this embodiment Z is hydroxy, di-[(1-3C]alkylamino(for example dimethylamino) or heterocyclyl (for example a fullysaturated 4, 5, 6 or 7-membered monocyclic heterocyclyl group containing1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, such aspyrrolidin-1-yl).

Particular compounds of the invention are, for example, one or morequinazoline derivatives of the Formula I selected from:

-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-4[(dimethylamino)acetyl]morpholin-3-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ol;-   1-[((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)carbonyl]cyclopropanol;-   3-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol;-   (2S)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(ethoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   N-[3-chloro(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   2-{(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}oxy)quinazolin-4-amine;-   2-{(3R)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}quinazolin-4-amine;-   N-[3-chloro-4-(1,3-thiazol-1-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-[(2R)-2-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   N-[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-{(3S)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;-   2-{(3R)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;-   N-[3-chloro-1-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;-   (2R)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{(1S)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{(1R)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2S)-2-({[4-{3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-{3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-{3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-{3-chloro-4[(3-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;-   2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;-   2-(4-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[4-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[4-({[4-{3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-methyl(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-{3-methyl-4[(5-methylisoxazol-3-yl)methoxy]phenyl}quinazolin-4-amine;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(3R)-3-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine;-   (N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3S)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   2-(S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine;-   2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   2-[(2R)-2-({[4-({3-chloro-4[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(3R)-3-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)morpholin-4-yl]-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;    and-   2-[(2R)-4-methyl-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperazin-1-yl]-2-oxoethanol;    or a pharmaceutically acceptable salt thereof.

Further particular compounds of the invention are, for example, one ormore quinazoline derivatives of the Formula I selected from:

-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-4[(dimethylamino)acetyl)]morpholin-3-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   1-((2R)-2-{[(4-{[3-chloro-4-pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ol;-   1-[((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)carbonyl]cyclopropanol;-   (2S)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-[(2R)-2-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-{(3S)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;    and-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;    or a pharmaceutically acceptable salt thereof.

Further particular compounds of the invention are, for example, one ormore quinazoline derivatives of the Formula I selected from:

-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ol;-   1-[((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)carbonyl]cyclopropanol;-   3-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol;-   (2S)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(ethoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   2-{(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;-   2-{(3R)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;-   N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-{(3S)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;-   2-{(3R)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;-   (2R)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{(1S)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{(1R)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[4-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[4-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-methylpyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-{3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}quinazolin-4-amine;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(3R)-3-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3S)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   (N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3S)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-anine;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   2-(S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-(I{[4-({3-chloro-4[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(3R)-3-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)morpholin-4-yl]-2-oxoethanol;-   2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;    and-   2-[(2R)-4-methyl-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperazin-1-yl]-2-oxoethanol;    or a pharmaceutically acceptable salt thereof.

Further particular compounds of the invention are, for example, one ormore quinazoline derivatives of the Formula I selected from:

-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ol;-   1-[((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)carbonyl]cyclopropanol;-   3-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   (2R)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{(1S)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{(1R)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl    44[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol    trifluoroacetate;    or a pharmaceutically active salt thereof.

Further particular compounds of the invention are, for example, one ormore quinazoline derivatives of the Formula I selected from:

-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   3-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   (2R)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;    and-   2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;    or a pharmaceutically active salt thereof.

Further particular compounds of the invention are, for example, one ormore quinazoline derivatives of the Formula I selected from:

-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;-   2-((2S)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;-   2-[(2S)-2-({[4-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;-   2-(4-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-{3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine;-   2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;-   N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;-   2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2S)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;    and-   2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;    or a pharmaceutically active salt thereof.

Further particular compounds of the invention are, for example, one ormore quinazoline derivatives of the Formula I selected from:

-   2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;-   2-[(2R)-2-({[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;-   2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;    and-   2-[(2S)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;    or a pharmaceutically active salt thereof.

A further particular compound of the invention is, for example, aquinazoline derivative of the Formula I selected from:

-   2-{(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;    and-   2-{(3R)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;    or a pharmaceutically acceptable salt thereof.

A further particular embodiment of the compounds of Formula I is aquinazoline derivative of the Formula Id:

wherein:

R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within aR¹ substituent are optionally separated by the insertion into the chainof a group selected from O, S, SO, SO₂, N(R³), CO, CON(R³), N(R³)CO,SO₂N(R³) and N(R³)SO₂, wherein R³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino;

Y is selected from hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyl and (2-4C)alkynyl;

a is 0, 1, 2 or 3 or 4;

each R², which may be the same or different, is selected from halogeno,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;

X² is a direct bond or is selected from O, S, OC(R⁴)₂, SC(R⁴)₂, SO, SO₂,N(R⁴), CO and N(R⁴)C(R⁴)₂ wherein each R⁴, which may be the same ordifferent, is selected from hydrogen or (1-6C)alkyl, and Q² is aryl orheteroaryl,

and wherein Q² optionally bears one or more substituents (for example 1,2 or 3), which may be the same or different, selected from halogeno,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, formyl,mercapto, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵

wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶), whereinR⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl,N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any CH₂ or CH₃ group within —X²-Q² optionally bears on eachsaid CH₂ or CH₃ one or more (for example 1, 2, or 3) halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

X¹ is a direct bond or C(R⁷)₂, wherein each R⁷, which may be the same ordifferent, is selected from hydrogen and (1-4C)alkyl;

ring Q¹ is a 4, 5, 6 or 7 membered saturated or partially unsaturatedheterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or2 additional heteroatoms selected from O, S and N, and which ring islinked to the group X¹ by a ring carbon;

X³ is a group of the formula:—(CR⁸R⁹)_(p)—(CR¹⁰R¹¹)_(q)—

wherein p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4,

each of R⁸, R⁹, R¹⁰ and R¹¹, which may be the same or different, isselected from hydrogen and (1-6C)alkyl, and

Z is selected from amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino andheterocyclyl, provided that when p and q are both 0, then Z isheterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Zsubstituent are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹³), CO, —C═C— and —C≡C— whereinR¹³ is hydrogen or (1-6C)alkyl,

and wherein any CH₂ or CH₃ group within any Z, X¹ or X³ group, otherthan a CH₂ group within a heterocyclyl ring, optionally bears on eachsaid CH₂ or CH₃ group one or more halogeno or (1-6C)alkyl substituentsor a substituent selected from hydroxy, cyano, amino, carboxy,carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group represented by Q¹ or within a Zsubstituent optionally bears one or more (for example 1, 2 or 3)substituents which may be the same or different, selected from halogeno,trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto,(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴

wherein X⁶ is a direct bond or is selected from O, CO, SO₂ and N(R¹⁵),wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ is halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl,

and wherein any heterocyclyl group represented by Q¹ or within a Zsubstituent optionally bears 1 or 2 oxo or thioxo substituents;

or a pharmaceutically acceptable salt thereof.

In this embodiment a particular value for Q² is phenyl or a 5 or 6membered heteroaryl ring containing 1 nitrogen heteroatom and optionally1 additional heteroatom selected from O, S and N, and wherein Q²optionally bears one or more substituents as defined above.

More particularly, in this embodiment Q² is selected from phenyl,pyridyl (such as 2- or 3-pyridyl), pyrazinyl (such as 2-pyrazinyl),1,3-thiazolyl (such as 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or1,3-thiazol-5-yl) and isoxazolyl (such as 3-isoxazolyl, 4 isoxazolyl or5-isoxazolyl), and wherein Q² optionally bears one or more substituentsas defined above. For example, in this embodiment, Q² may be selectedfrom 2-fluorophenyl, 3-fluorophenyl, 2-pyridyl, 3-pyridyl,6-methylpyrid-2-yl, 6-methylpyrid-3-yl, 2-pyrazinyl, 1,3-thiazol-2-yl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 5-methyl-3-isoxazolyl.

In this embodiment a particular value for X² is O or OCH₂.

In this embodiment a particular value for a is 0 or 1, more particularly0.

In this embodiment, a particular value for Y is halogeno (such as chloroor fluoro, particularly chloro) or (1-4C)alkyl (such as methyl).

In this embodiment R⁸, R⁹, R¹⁰ and R¹¹ are particularly hydrogen. Thus,in this embodiment, a particular value for X³ is —(CH₂)_(r)—, wherein ris 1, 2, 3, 4, 5 or 6. More particularly, in this embodiment X³ is—CH₂—.

In this embodiment, the sum of p and q is suitably 1, 2, 3, 4, 5, or 6.When the sum of p and q is 1, then Z is particularly heterocyclyl.

In this embodiment, the group Z-X³— is suitably dimethylaminomethyl orpyrrolidin-1-ylmethyl.

In this embodiment, Q¹ is particularly a 5 or 6 membered saturatedheterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or2 (for example 1) additional heteroatoms independently selected fromoxygen, nitrogen and sulfur, and which ring is linked to the group X¹ bya ring carbon. For example, Q¹ is selected from azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl andthiomorpholinyl (particularly pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl).

Particular compounds of the invention are, for example, one or morequinazoline derivatives of the Formula Id selected from:

-   N-[3-chloro(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-4-[(dimethylamino)acetyl]morpholin-3-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}oxy)quinazolin-4-amine;-   N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;-   N-{3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-{3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin    4-amine;-   N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-({(25)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;-   5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;-   5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;-   N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;    and-   N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;    or a pharmaceutically active salt thereof.

A quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Suitable processes include, for example, those illustrated inInternational Patent Applications WO 96/15118, WO01/94341, WO03/040108and WO03/040109. Such processes, when used to prepare a quinazolinederivative of the Formula I are provided as a further feature of theinvention and are illustrated by the following representative processvariants in which, unless otherwise stated, R¹, R², X¹, X², X³, Y, Q¹,Q², a and Z have any of the meanings defined hereinbefore. Necessarystarting materials may be obtained by standard procedures of organicchemistry. The preparation of such starting materials is described inconjunction with the following representative process variants andwithin the accompanying Examples. Alternatively necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist.Process (a) The coupling, conveniently in the presence of a suitablebase, of a quinazoline of the formula II:

wherein R¹, R², X¹, X², Y, a, Q¹ and Q² have any of the meanings definedhereinbefore except that any functional group is protected if necessary,with a carboxylic acid of the formula III, or a reactive derivativethereof.Z-X³—COOH  III

wherein Z and X³ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary;

or

Process (b) for the preparation of those compounds of the Formula Iwherein X² is OC(R⁴)₂, SC(R⁴)₂ or N(R⁴)C(R⁴)₂, the reaction,conveniently in the presence of a suitable base, of a quinazoline of theformula IV:

wherein X^(2a) is O, S or N(R⁴) and R¹, R², X¹, X³, Z, Y, a and Q¹ haveany of the meanings defined hereinbefore except that any functionalgroup is protected if necessary, with a compound of the formula V:Q²-C(R⁴)₂-L¹  Vwherein L¹ is a suitable displaceable group and Q² and R⁴ have any ofthe meanings defined hereinbefore except that any functional group isprotected if necessary; orProcess (c) The coupling of a quinazoline of the formula VI:

wherein L¹ is a suitable displaceable group and R¹, R², X¹, X², X³, Y,a, Q¹ and Q² have any of the meanings defined hereinbefore except thatany functional group is protected if necessary, with a compound of theformula VII, or a reactive derivative thereof:Z-H  VII

wherein Z has any of the meanings defined hereinbefore except that anyfunctional group is protected if necessary; orProcess (d) for the preparation of those compounds of the Formula Iwherein X² is O and Q² is 2-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 2-pyrazinyl or 3-pyridazinyl, the reaction, conveniently inthe presence of a suitable base and a suitable catalyst, of aquinazoline of the formula IV:

wherein X^(2a) is O and wherein R¹, R², X¹, X³, Z, Y, a and Q¹ have anyof the meanings defined hereinbefore except that any functional group isprotected if necessary, with 2-bromopyridine, 4-bromopyridine,2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or3-chloropyridazine;

and thereafter, if necessary:

(i) converting a quinazoline derivative of the formula I into anotherquinazoline derivative of the formula I;

(ii) removing any protecting group that is present by conventionalmeans;

(iii) forming a pharmaceutically acceptable salt.

Specific conditions for the above reactions are as follows:

Process (a)

The coupling reaction is conveniently carried out in the presence of asuitable coupling agent, such as a carbodiimide, or a suitable peptidecoupling agent, for exampleO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HATU) or a carbodiimide such asdicyclohexylcarbodiimide, optionally in the presence of a catalyst suchas dimethylaminopyridine or 4-pyrrolidinopyridine.

The coupling reaction is conveniently carried out in the presence of asuitable base. A suitable base is, for example, an organic amine basesuch as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, di-isopropylethylamine,N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example,an alkali or alkaline earth metal carbonate, for example sodiumcarbonate, potassium carbonate, cesium carbonate, calcium carbonate.

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example an ester such as ethyl acetate, ahalogenated solvent such as methylene chloride, chloroform or carbontetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulfoxide. The reaction is conveniently carried out at atemperature in the range, for example, from 0 to 120° C., convenientlyat or near ambient temperature.

By the term “reactive derivative” of the carboxylic acid of the formulaIII is meant a carboxylic acid derivative that will react with thequinazoline of formula II to give the corresponding amide. A suitablereactive derivative of a carboxylic acid of the formula III is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an active ester, for example an ester formed by the reaction of the acidand a phenol such as pentafluorophenol, an ester such aspentafluorophenyl trifluoroacetate or an alcohol such as methanol,ethanol, isopropanol, butanol or N-hydroxybenzotriazole; or an acylazide, for example an azide formed by the reaction of the acid and azidesuch as diphenylphosphoryl azide; an acyl cyanide, for example a cyanideformed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide. The reaction of such reactive derivatives ofcarboxylic acid with amines (such as a compound of the formula II) iswell known in the art, for example they may be reacted in the presenceof a base, such as those described above, and in a suitable solvent,such as those described above. The reaction may conveniently beperformed at a temperature as described above.

The quinazoline of the formula II may be obtained by conventionalprocedures. For example, the reaction, conveniently in the presence of asuitable base, of a quinazoline of the formula IIa:

wherein R⁵, R², Q², X², a and Y have any of the meanings definedhereinbefore except that any functional group is protected if necessary,and L² is a suitable displaceable group, with an alcohol of the formulaIIb:

wherein Q¹ and X¹ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary; and thereafter, ifnecessary removing any protecting group that is present by conventionalmeans.

A suitable displaceable group L² in the quinazoline of formula IIa isfor example halogeno or a sulfonyloxy group, for example fluoro, chloro,methylsulfonyloxy or toluene-4-sulfonyloxy group. A particular group Lis fluoro or chloro, more particularly flouro.

A suitable base for the reaction a quinazoline of the formula IIa andthe alcohol of the formula IIb includes, for example a strongnon-nucleophilic base such as an alkali metal hydride, for examplesodium hydride, or an alkali metal amide, for example lithiumdi-isopropylamide (LDA).

The reaction a quinazoline of the formula IIa and the alcohol of theformula IIb is conveniently carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, ora dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.The reaction is conveniently carried out at a temperature in the rangeof, for example, 10 to 250° C., preferably in the range 40 to 150° C.Conveniently, this reaction may also be performed by heating thereactants in a sealed vessel using a suitable heating apparatus such asa microwave heater.

Conveniently, the reaction a quinazoline of the formula IIa and thealcohol of the formula IIb is performed in the presence of a suitablecatalyst, for example a crown ether such as 15-crown-5.

Alcohols of the formula IIb are commercially available compounds or theyare known in the literature, or they can be can be prepared by standardprocesses known in the art. For example when X¹ is CH₂ by the reductionof the corresponding acid or ester thereof as illustrated in ReactionScheme 1:

The quinazoline of the formula IIa may be obtained by conventionalprocedures. For example, a quinazoline of the formula IIc:

wherein L² and L³ are displaceable groups, and L³ is more labile thanL², may be reacted with a compound of the formula IId:

wherein Q², R¹, R², Y, a and X² have any of the meanings definedhereinbefore except that any functional group is protected if necessary,whereafter any protecting group that is present is removed byconventional means.

A suitable displaceable group L² is as hereinbefore defined,particularly fluoro. A suitable displaceable group L³ is, for example, ahalogeno particularly chloro), alkoxy, aryloxy, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,alkylsulfonyloxy or arylsulfonyloxy group, for example a chloro, bromo,methoxy, phenoxy, pentafluorophenoxy, methylthio, methanesulfonyl,methanesulfonyloxy or toluene-4-sulfonyloxy group.

The reaction is conveniently carried out in the presence of an acid.Suitable acids include, for example hydrogen chloride gas (convenientlydissolved in diethyl ether or dioxane) or hydrochloric acid.

Alternatively the quinazoline derivative of the formula IIc, wherein L³is halogeno (for example chloro), may be reacted with the compound ofthe formula IId in the absence of an acid or a base. In this reactiondisplacement of the halogeno leaving group L³ results in the formationof the acid HL³ in-situ and the autocatalysis of the reaction.

Alternatively, the reaction of the quinazoline of formula IIc with thecompound of formula IId may be carried out in the presence of a suitablebase. A suitable base is, for example, an organic amine base such as,for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, di-isopropylethylamine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkalineearth metal carbonate, for example sodium carbonate, potassiumcarbonate, cesium carbonate, calcium carbonate, or, for example, analkali metal hydride, for example sodium hydride.

The above reactions are conveniently carried out in the presence of asuitable inert solvent or diluent, for example an alcohol or ester suchas methanol, ethanol, isopropanol or ethyl acetate, a halogenatedsolvent such as methylene chloride, chloroform or carbon tetrachloride,an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent suchas toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.The above reactions are conveniently carried out at a temperature in therange, for example, 0 to 250° C., conveniently in the range 40 to 80° C.or, preferably, at or near the reflux temperature of the solvent whenused.

The quinazoline of formula IIc may be obtained using conventionalmethods, for example, when R¹ is hydrogen, L² is fluoro and L³ ishalogeno, 5-fluoro-3,4-dihydroquinazolin-4-one may be reacted with asuitable halogenating agent such as thionyl chloride, phosphorylchloride or a mixture of carbon tetrachloride and triphenylphosphine.The 5-fluoro-3,4-dihydroquinazoline starting material is commerciallyavailable or can be prepared using conventional methods, for example asdescribed in J. Org. Chem. 1952, 17, 164-176.

Compounds of the formula IId are commercially available compounds orthey are known in the literature, or they can be can be prepared bystandard processes known in the art. For example, the compound of theformula IId wherein X² is O, S, N(R⁴), OC(R⁴)₂, SC(R⁴)₂ or N(R⁴)C(R⁴)₂may be prepared in accordance with Reaction Scheme 2:

wherein L⁴ is a suitable displaceable group as hereinbefore defined (forexample halogeno such as chloro) and Q², X², Y, R² and a are ashereinbefore defined, except any functional group is protected ifnecessary, and whereafter any protecting group that is present isremoved by conventional means.

(i) The compounds of the formula HX²Q² are commercially available, orthey are known in the literature, or can be prepared using well knownprocesses in the art. For example compounds of the formula Q²CH₂OH maybe prepared using known methods, for example by reduction of thecorresponding ester of the formula Q²COOR, wherein R is, for example(1-6C)alkyl, or benzyl, with a suitable reducing agent, for examplesodium borohydride, followed by ester hydrolysis.

(ii) The reduction of the nitro group in step (ii) may be carried outunder standard conditions, for example by catalytic hydrogenation over aplatinum/carbon, palladium/carbon or nickel catalyst, treatment with ametal such as iron, titanium chloride, tin II chloride or indium, ortreatment with another suitable reducing agent such as sodiumdithionite.

Compounds of the formula IId wherein X² is OC(R⁴)₂, SC(R⁴)₂ orN(R⁴)C(R⁴)₂ may, for example, be prepared in accordance with ReactionScheme 3:

wherein L¹ is a suitable leaving group as defined hereinafter inrelation to Process (b), and X^(2a) is as hereinbefore defined inProcess (b).Step (i): Analogous conditions to those used in Process (b)Step (ii) Analogous conditions to those used in Reaction Scheme 2.

Compounds of the formula IId wherein X² is OC(R⁴)₂ may also be preparedby coupling the appropriate starting nitro phenol in Reaction Scheme 3(X^(2a)H is OH) with a compound of the formula Q²C(R⁴)₂OH, convenientlyin the presence of a suitable dehydrating agent. A suitable dehydratingagent is, for example, a carbodiimide reagent such asdicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azocompound such as diethyl or di-tert-butyl azodicarboxylate and aphosphine such as triphenylphosphine. The reaction is convenientlycarried out in the presence of a suitable inert solvent or diluent, forexample a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride and at a temperature in the range, for example, 0to 150° C., preferably at or near ambient temperature.

Alternatively the quinazoline of formula II wherein X² is OC(R⁴)₂,SC(R⁴)₂ or N(R⁴)C(R⁴)₂ and X¹ is a direct bond may be prepared accordingto Reaction Scheme 4:

wherein Pg is a suitable amine protecting group (for exampletert-butoxycarbonyl (BOC)), and R¹, R², R⁴, X¹, X², X^(2a), Q¹, Q², L¹,L², L³, a and Y are as hereinbefore defined except that any functionalgroup is protected if necessary, whereafter any protecting group that ispresent is removed by conventional means.Notes:Step (i) Analogous conditions to the reaction of the quinazoline of theformula IIc with the compound of the formula IId described above.Step (ii) Analogous conditions to those used in the reaction of thecompound of formula IIa with the alcohol of the formula IIb describedabove.Step (iii) Analogous conditions to those used in Process (b).Step (iv) Removal of protecting group by conventional means, for examplewhen Pg is a BOC group by treatment with a suitable acid such astrifluoroacetic acid.

Compounds of the formula IVa are commercially available compounds orthey are known in the literature, or they can be can be prepared bystandard processes known in the art.

Process (b)

A suitable displaceable group L¹ in the compound of the formula V is forexample halogeno or a sulfonyloxy group, for example fluoro, chloro,methylsulfonyloxy or toluene-4-sulfonyloxy group. A particular group Lis fluoro or chloro or methylsulfonyloxy.

The reaction of the quinazoline of formula IV with the compound offormula V is conveniently carried out in the presence of a suitable basesuch as, for example, a base as described in relation to Process (a)such as an alkali or alkaline earth metal carbonate, for examplepotassium carbonate.

The reaction a quinazoline of the formula IV and the compound of theformula V is conveniently carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, ora dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.The reaction is conveniently carried out at a temperature in the rangeof, for example, from 25 to 100° C., conveniently at or near ambienttemperature.

The reaction a quinazoline of the formula IV and the compound of theformula V is conveniently carried out in the presence of a suitablecatalyst, for example a crown ether such as 18-crown-6.

Compounds of the formula V are commercially available compounds or theyare known in the literature, or they can be can be prepared by standardprocesses known in the art. The quinazoline of the formula IV may beprepared using conventional methods, for example, by reacting a compoundof the formula IVb:

wherein R¹, R², X¹, X^(2a), Q¹, a and Y are as hereinbefore definedexcept that any functional group is protected if necessary, with acarboxylic acid of the formula III, or a reactive derivative thereof:Z-X³—COOH  III

wherein Z and X³ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary and whereafter anyprotecting group that is present is removed by conventional means.

The reaction of the quinazoline of the formula IVb and the compound offormula III is conveniently carried using analogous conditions to thosedescribed above for Process (a).

The quinazoline of the formula IVb may be prepared according to ReactionScheme 5.

wherein R¹, R², R⁴, X¹, X^(2a), Q¹, a and Y are as hereinbefore definedexcept that any functional group is protected if necessary, whereafterany protecting group that is present is removed by conventional means.

Notes:

Step (i): Analogous conditions to those used in the reaction of thecompound of formula IIa with the alcohol of the formula IIb describedabove in relation to process (a).

The compound of formula IVc may be prepared using Reaction Scheme 4.

The alcohol of the formula IVd are commercially available compounds orthey are known in the literature, or they can be can be prepared bystandard processes known in the art.

Process (c)

A suitable displaceable group L¹ in the compound of the formula VI isfor example halogeno or a sulfonyloxy group, for example fluoro, chloro,methylsulfonyloxy or toluene-4-sulfonyloxy group. A particular group L¹is fluoro or chloro or methylsulfonyloxy.

The reaction of the quinazoline of formula VI with the compound offormula VI is conveniently carried out in the presence of a suitablecatalyst such as, for example, tetra-n-butylammonium iodide or potassiumiodide.

The reaction a quinazoline of the formula IV and the compound of theformula V is conveniently carried out in the presence of a suitableinert solvent or diluent, for example an ether such as tetrahydrofuranor 1,4-dioxane, an aromatic solvent such as toluene, or a dipolaraprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction isconveniently carried out at a temperature in the range of, for example,from 25 to 150° C., conveniently at about 100° C.

The quinazoline of the formula VI may be prepared using conventionalmethods, for example, as discussed above.

Compounds of the formula VII are commercially available compounds orthey are known in the literature, or they can be can be prepared bystandard processes known in the art.

Process (d)

The reaction is conveniently carried out in the presence of a suitablebase. A suitable base is, for example, an alkali or alkaline earth metalcarbonate, for example sodium carbonate, potassium carbonate, cesiumcarbonate or calcium carbonate.

A suitable catalyst for the reaction of a quinazoline of the formula IVand 2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or3-chloropyridazine is for example a crown ether such as 18-crown-6.

A suitable catalyst for the reaction of a quinazoline of the formula IVand 2-bromopyridine or 4-bromopyridine is a palladium catalyst, forexample a catalyst formed in situ by the reaction ofbis(dibenzylideneacetone)palladium and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.

The reaction is conveniently performed in a suitable inert solvent ordiluent, for example an ether such as tetrahydrofuran or 1,4-dioxane, ora dipolar aprotic solvent such as acetonitrile.

Suitably the reaction is carried out at a temperature of, for example 0to 180° C., particularly 20° C. to the reflux temperature of thesolvent/diluent. Conveniently the reaction may also be carried out byheating the reactants in a sealed vessel using a suitable heatingapparatus such as a microwave heater.

The quinazoline derivative of the Formula I may be obtained from theabove processes in the form of the free base or alternatively it may beobtained in the form of a salt, an acid addition salt. When it isdesired to obtain the free base from a salt of the compound of FormulaI, the salt may be treated with a suitable base, for example, an alkalior alkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide, or by treatment with ammonia for example using amethanolic ammonia solution such as 7N ammonia in methanol.

The protecting groups used in the processes above may in general bechosen from any of the groups described in the literature or known tothe skilled chemist as appropriate for the protection of the group inquestion and may be introduced by conventional methods. Protectinggroups may be removed by any convenient method as described in theliterature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned are, of course, within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, and tert-butyl); loweralkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl andisobutoxymethyl); lower acyloxy-lower alkyl groups, (for exampleacetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (forexample 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl);aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(loweralkyl)silyl groups (for example trimethylsilyl andtert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (forexample trimethylsilylethyl); and (2-6C)alkenyl groups (for exampleallyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed cleavage.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for exampletrimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (forexample benzyl) groups.

Examples of amino protecting groups include formyl, aryl-lower alkylgroups (for example benzyl and substituted benzyl, 4-methoxybenzyl,2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); lower alkanoyloxyalkyl groups (forexample pivaloyloxymethyl); trialkylsilyl (for example trimethylsilyland tert-butyldimethylsilyl); alkylidene (for example methylidene) andbenzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such as2-nitrobenzyloxycarbonyl. For example a tert butoxycarbonyl protectinggroup may be removed from an amino group by an acid catalysed hydrolysisusing trifluoroacetic acid.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by J.March, published by John Wiley & Sons 1992, for general guidance onreaction conditions and reagents and to Protective Groups in OrganicSynthesis, 2^(nd) Edition, by T. Green et al., also published by JohnWiley & Son, for general guidance on protecting groups.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group.

When a pharmaceutically-acceptable salt of a quinazoline derivative ofthe formula I is required, for example an acid-addition salt, it may beobtained by, for example, reaction of said quinazoline derivative with asuitable acid using a conventional procedure.

As mentioned hereinbefore some of the compounds according to the presentinvention may contain one or more chiral centers and may therefore existas stereoisomers (for example when Q¹ is pyrrolidin-2-yl). Stereoisomersmay be separated using conventional techniques, e.g. chromatography orfractional crystallisation. The enantiomers may be isolated byseparation of a racemate for example by fractional crystallisation,resolution or HPLC. The diastereoisomers may be isolated by separationby virtue of the different physical properties of the diastereoisomers,for example, by fractional crystallisation, HPLC or flashchromatography. Alternatively particular stereoisomers may be made bychiral synthesis from chiral starting materials under conditions whichwill not cause racemisation or epimerisation, or by derivatisation, witha chiral reagent. When a specific stereoisomer is isolated it issuitably isolated substantially free for other stereoisomers, forexample containing less than 20%, particularly less than 10% and moreparticularly less than 5% by weight of other stereoisomers.

In the section above relating to the preparation of the quinazolinederivative of Formula I, the expression “inert solvent” refers to asolvent which does not react with the starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product.

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative and in some occasions, moreconvenient manner, the individual process steps mentioned hereinbeforemay be performed in different order, and/or the individual reactions maybe performed at different stage in the overall route (i.e. chemicaltransformations may be performed upon different intermediates to thoseassociated hereinbefore with a particular reaction).

Certain intermediates used in the processes described above are noveland form a further feature of the present invention. Accordingly thereis provided a compound selected from a compound the formulae II, IV, IVband IVc as hereinbefore defined, or a salt thereof, provided that in thecompound of formula II, X¹ is C(R⁷)₂, wherein R⁷ is as hereinbeforedefined. The intermediate may be in the form of a salt of theintermediate. Such salts need not be a pharmaceutically acceptable salt.For example it may be useful to prepare an intermediate in the form of apharmaceutically non-acceptable salt if, for example, such salts areuseful in the manufacture of a compound of Formula I.

Biological Assays

The inhibitory activities of compounds were assessed in non-cell basedprotein tyrosine kinase assays as well as in cell based proliferationassays before their in vivo activity was assessed in Xenograft studies.

a) Protein Tyrosine Kinase Phosphorylation Assays

This test measures the ability of a test compound to inhibit thephosphorylation of a tyrosine containing polypeptide substrate by EGFRtyrosine kinase enzyme.

Recombinant intracellular fragments of EGFR, erbB2 and erbB4 (accessionnumbers X00588, X03363 and L07868 respectively) were cloned andexpressed in the baculovirus/Sf21 system. Lysates were prepared fromthese cells by treatment with ice-cold lysis buffer (20 mMN-2-hydroxyethylpiperizine-N′-2-ethanesulfonic acid (HEPES) pH7.5, 150mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl₂, 1 mM ethyleneglycol-bis(β-aminoethyl ether)N′,N′,N′,N′-tetraacetic acid (EGTA), plusprotease inhibitors and then cleared by centrifugation.

Constitutive kinase activity of these recombinant proteins wasdetermined by their ability to phosphorylate a synthetic peptide (madeup of a random co-polymer of Glutamic Acid, Alanine and Tyrosine in theratio of 6:3:1). Specifically, Maxisorb™ 96-well immunoplates werecoated with synthetic peptide (0.2 μg of peptide in a 2000 μl phosphatebuffered saline (PBS) solution and incubated at 4° C. overnight). Plateswere washed in 50 mM HEPES pH 7.4 at room temperature to remove anyexcess unbound synthetic peptide. EGFR or erbB2 activities were assessedby incubation in peptide coated plates for 20 minutes at roomtemperature in 100 mM HEPES pH 7.4 at room temperature, adenosinetrisphosphate (ATP) at Km concentration for the respective enzyme, 10 mMMnCl₂, 0.1 mM Na₃VO₄, 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100with test compound in DMSO (final concentration of 2.5%). Reactions wereterminated by the removal of the liquid components of the assay followedby washing of the plates with PBS-T (phosphate buffered saline with 0.5%Tween 20).

The immobilised phospho-peptide product of the reaction was detected byimmunological methods. Firstly, plates were incubated for 90 minutes atroom temperature with anti-phosphotyrosine primary antibodies that wereraised in the mouse (4G10 from Upstate Biotechnology). Followingextensive washing, plates were treated with Horseradish Peroxidase (HRP)conjugated sheep anti-mouse secondary antibody (NXA931 from Amersham)for 60 minutes at room temperature. After further washing, HRP activityin each well of the plate was measured colorimetrically using22′-Azino-di-[3-ethylbenzthiazoline sulfonate (6)]diammonium saltcrystals (ABTS™ from Roche) as a substrate. Quantification of colourdevelopment and thus enzyme activity was achieved by the measurement ofabsorbance at 405 nm on a Molecular Devices ThermoMax microplate reader.Kinase inhibition for a given compound was expressed as an IC₅₀ value.This was determined by calculation of the concentration of compound thatwas required to give 50% inhibition of phosphorylation in this assay.The range of phosphorylation was calculated from the positive (vehicleplus ATP) and negative (vehicle minus ATP) control values.

b) EGFR Driven KB Cell Proliferation Assay

This assay measures the ability of a test compound to inhibit theproliferation of KB cells (human naso-pharangeal carcinoma obtained fromthe American Type Culture Collection (ATCC)).

KB cells were cultured in Dulbecco's modified Eagle's medium (DMEM)containing 10% foetal calf serum, 2 mM glutamine and non-essential aminoacids at 37° C. in a 7.5% CO₂ air incubator. Cells were harvested fromthe stock flasks using Trypsin/ethylaminediaminetetraacetic acid (EDTA).Cell density was measured using a haemocytometer and viability wascalculated using trypan blue solution before being seeded at a densityof 1.25×10³ cells per well of a 96 well plate in DMEM containing 2.5%charcoal stripped serum, 1 mM glutamine and non-essential amino acids at37° C. in 7.5% CO₂ and allowed to settle for 4 hours.

Following adhesion to the plate, the cells are treated with or withoutEGF (final concentration of 1 ng/ml) and with or without compound at arange of concentrations in dimethylsulfoxide (DMSO) (0.1% final) beforeincubation for 4 days. Following the incubation period, cell numberswere determined by addition of 50 μl of3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)(stock 5 mg/ml) for 2 hours. MTT solution was then tipped off, the plategently tapped dry and the cells dissolved upon the addition of 100 μl ofDMSO.

Absorbance of the solubilised cells was read at 540 nm using a MolecularDevices ThermoMax microplate reader. Inhibition of proliferation wasexpressed as an IC₅₀ value. This was determined by calculation of theconcentration of compound that was required to give 50% inhibition ofproliferation. The range of proliferation was calculated from thepositive (vehicle plus EGF) and negative (vehicle minus EGF) controlvalues.

c) Clone 24 Phospho-erbB2 Cell Assay

This immunofluorescence end point assay measures the ability of a testcompound to inhibit the phosphorylation of erbB2 in a MCF7 (breastcarcinoma) derived cell line which was generated by transfecting MCF7cells with the full length erbB2 gene using standard methods to give acell line that overexpresses full length wild type erbB2 protein(hereinafter ‘Clone 24’ cells).

Clone 24 cells were cultured in Growth Medium (phenol red freeDulbecco's modified Eagle's medium (DMEM) containing 10% foetal bovineserum, 2 mM glutamine and 1.2 mg/ml G418) in a 7.5% CO₂ air incubator at37° C. Cells were harvested from T75 stock flasks by washing once in PBS(phosphate buffered saline, pH7.4, Gibco No. 10010-015) and harvestedusing 2 mls of Trypsin (1.25 mg/ml)/ethylaminediaminetetraacetic acid(EDTA) (0.8 mg/ml) solution. The cells were resuspended in GrowthMedium. Cell density was measured using a haemocytometer and viabilitywas calculated using Trypan Blue solution before being further dilutedin Growth Medium and seeded at a density of 1×10⁴ cells per well (in 100ul) into clear bottomed 96 well plates (Packard, No. 6005182).

3 days later, Growth Medium was removed from the wells and replaced with100 ul Assay Medium (phenol red free DMEM, 2 mM glutamine, 1.2 mg/mlG418) either with or without erbB inhibitor compound. Plates werereturned to the incubator for 4 hrs and then 20 μl of 20% formaldehydesolution in PBS was added to each well and the plate was left at roomtemperature for 30 minutes. This fixative solution was removed with amultichannel pipette, 100 μl of PBS was added to each well and thenremoved with a multichannel pipette and then 50 μl PBS was added to eachwell. Plates were then sealed and stored for up to 2 weeks at 4° C.

Immunostaining was performed at room temperature. Wells were washed oncewith 200 μl PBS/Tween 20 (made by adding 1 sachet of PBS/Tween drypowder (Sigma, No. P3563) to 1 L of double distilled H₂O) using a platewasher then 200 μl Blocking Solution (5% Marvel dried skimmed milk(Nestle) in PBS/Tween 20) was added and incubated for 10 minutes.Blocking Solution was removed using a plate washer and 200 μl of 0.5%Triton X-100/PBS was added to permeabalise the cells. After 10 minutes,the plate was washed with 200 μl PBS/Tween 20 and then 200 μl BlockingSolution was added once again and incubated for 15 minutes. Followingremoval of the Blocking Solution with a plate washer, 30 μl of rabbitpolyclonal anti-phospho ErbB2 IgG antibody (epitope phospho-Tyr 1248,SantaCruz, No. SC-12352-R), diluted 1:250 in Blocking Solution, wasadded to each well and incubated for 2 hours. Then this primary antibodysolution was removed from the wells using a plate washer followed by two200 μl PBS/Tween 20 washes using a plate washer. Then 30 μl ofAlexa-Fluor 488 goat anti-rabbit IgG secondary antibody (MolecularProbes, No. A-11008), diluted 1:750 in Blocking Solution, was added toeach well. From now onwards, wherever possible, plates were protectedfrom light exposure, at this stage by sealing with black backing tape.The plates were incubated for 45 minutes and then the secondary antibodysolution was removed from the wells followed by two 200 ul PBS/Tween 20washes using a plate washer. Then 100 μl PBS was added to each plate,incubated for 10 minutes and then removed using a plate washer. Then afurther 100 μl PBS was added to each plate and then, without prolongedincubation, removed using a plate washer. Then 50 μl of PBS was added toeach well and plates were resealed with black backing tape and storedfor up to 2 days at 4° C. before analysis.

The Fluorescence signal is each well was measured using an AcumenExplorer Instrument (Acumen Bioscience Ltd.), a plate reader that can beused to rapidly quantitate features of images generated bylaser-scanning. The instrument was set to measure the number offluorescent objects above a pre-set threshold value and this provided ameasure of the phosphorylation status of erbB2 protein. Fluorescencedose response data obtained with each compound was exported into asuitable software package (such as Origin) to perform curve fittinganalysis. Inhibition of erbB2 phosphorylation was expressed as an IC₅₀value. This was determined by calculation of the concentration ofcompound that was required to give 50% inhibition of erbB2phosphorylation signal.

d) In Vivo BT-474 Xenograft Assay

This assay measures the ability of a test compound to inhibit the growthof a BT-474 tumour cell xenograft (human mammary carcinoma obtained fromDr Baselga, Laboratorio Recerca Oncologica, Paseo Vail D'Hebron 119-129,Barcelona 08035, Spain) in Female Swiss athymic mice (Alderley Park,nu/nu genotype) (Baselga, J. et al. (1998) Cancer Research, 58,2825-2831).

Female Swiss athymic (nu/nu genotype) mice were bred and maintained inAlderley Park in negative pressure Isolators (PFI Systems Ltd.). Micewere housed in a barrier facility with 12 hr light/dark cycles andprovided with sterilised food and water ad libitum. All procedures wereperformed on mice of at least 8 weeks of age. BT-474 tumour cellxenografts were established in the hind flank of donor mice bysub-cutaneous injections of 1×10⁷ freshly cultured cells in 100 μl ofserum free media with 50% Matrigel per animal. On day 14 post-implant,mice were randomised into groups of 10 prior to the treatment withcompound or vehicle control that was administered once daily at 0.1ml/10 g body weight. Tumour volume was assessed twice weekly bybilateral Vernier calliper measurement, using the formula(length×width)—√(length×width)×(π/6), where length was the longestdiameter across the tumour, and width was the correspondingperpendicular. Growth inhibition from start of treatment was calculatedby comparison of the mean changes in tumour volume for the control andtreated groups, and statistical significance between the two groups wasevaluated using a Students t test.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general activity possessedby compounds of the Formula I, may be demonstrated at the followingconcentrations or doses in one or more of the above tests (a), (b) and(c):— Test (a):- IC₅₀ in the range, for example, 0.001-1 μM; Test (b):-IC₅₀ in the range, for example, 0.001-5 μM; Test (c):- IC₅₀ in therange, for example, 0.001-5 μM; Test (d):- activity in the range, forexample, 1-200 mg/kg/day;

No physiologically unacceptable toxicity was observed in Test (d) at theeffective dose for compounds tested of the present invention.Accordingly no untoward toxicological effects are expected when acompound of Formula I, or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore is administered at the dosage ranges definedhereinafter.

By way of example, Table A illustrates the activity of representativecompounds according to the invention. Column 2 of Table A shows IC₅₀data from Test (a) for the inhibition of EGFR tyrosine kinase proteinphosphorylation; column 3 shows IC₅₀ data from Test (a) for theinhibition of erbB2 tyrosine kinase protein phosphorylation; and column4 shows IC₅₀ data for inhibition of phosphorylation of erbB2 in a MCF7derived cell line in Test (c) described above: TABLE A IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) Test (a): Test (a): Test (c): Inhibition of Inhibition ofInhibition of EGFR tyrosine erbB2 tyrosine erbB2 tyrosine Example kinaseprotein kinase protein kinase protein Number phosphorylationphosphorylation phosphorylation 25 0.26 0.048 1.40 40 33.0 0.63 2.40 782.40 0.034 0.19

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a quinazoline derivative ofthe formula I, or a pharmaceutically-acceptable thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of aquinazoline derivative of the formula I will naturally vary according tothe nature and severity of the conditions, the age and sex of the animalor patient and the route of administration, according to well knownprinciples of medicine.

In using a quinazoline derivative of the formula I for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight isreceived, given if required in divided doses. In general lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration is however preferred, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

We have found that the compounds of the present invention possessanti-proliferative properties such as anti-cancer properties that arebelieved to arise from their erb-B, particularly EGFR and moreparticularly erbB2 receptor tyrosine kinase inhibitory activity.Furthermore, certain of the compounds according to the present inventionpossess substantially better potency against the erbB2 receptor tyrosinekinase, than against other tyrosine kinases enzymes, such as EGFRtyrosine kinase. Such compounds possess sufficient potency against theerbB2 receptor tyrosine kinase that they may be used in an amountsufficient to inhibit erbB2 receptor tyrosine kinase whilstdemonstrating little, or significantly lower, activity against othertyrosine kinases such as EGFR. Such compounds are likely to be usefulfor the selective inhibition of erbB2 receptor tyrosine kinase and arelikely to be useful for the effective treatment of, for example erbB2driven tumours. Accordingly, the compounds of the present invention areexpected to be useful in the treatment of diseases or medical conditionsmediated alone or in part by and erb-B, particularly erbB2 receptortyrosine kinases, i.e. the compounds may be used to produce a erb-B,particularly an erbB2, receptor tyrosine kinase inhibitory effect in awarm-blooded animal in need of such treatment. Thus the compounds of thepresent invention provide a method for the treatment of malignant cellscharacterised by inhibition of the erb-B, particularly erbB2, receptortyrosine kinase. Particularly the compounds of the invention may be usedto produce an anti-proliferative and/or pro-apoptotic and/oranti-invasive effect mediated alone or in part by the inhibition oferb-B, particularly erbB2, receptor tyrosine kinases. Particularly, thecompounds of the present invention are expected to be useful in theprevention or treatment of those tumours that are sensitive toinhibition of an erb-B, particularly the erbB2, receptor tyrosine kinasethat are involved in the signal transduction steps which driveproliferation and survival of these tumour cells. Accordingly thecompounds of the present invention are expected to be useful in thetreatment and/or prevention of a number of hyperproliferative disordersby providing an anti-proliferative effect. These disorders include, forexample psoriasis, benign prostatic hyperplasia (BPH), atherosclerosisand restenosis and, in particular, erb-B, more particularly erb-B2,receptor tyrosine kinase driven tumours. Such benign or malignanttumours may affect any tissue and include non-solid tumours such asleukaemia, multiple myeloma or lymphoma, and also solid tumours, forexample bile duct, bone, bladder, brain/CNS, breast, colorectal,cervical, endometrial, gastric, head and neck, hepatic, lung, muscle,neuronal, oesophageal, ovarian, pancreatic, pleural/peritonealmembranes, prostate, renal, skin, testicular, thyroid, uterine andvulval tumours.

According to this aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use as a medicament.

Thus according to this aspect of the invention there is provided the useof a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the production of ananti-proliferative effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, as hereinbefore defined.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in the production of ananti-proliferative effect in a warm-blooded animal such as man.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the production of ananti-proliferative effect which effect is produced alone or in part byinhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal suchas man.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect whicheffect is produced alone or in part by inhibiting erbB2 receptortyrosine kinase in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a quinazoline derivative of the formula I, or apharmaceutically acceptable salt thereof, as hereinbefore defined.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in the production of ananti-proliferative effect which effect is produced alone or in part byinhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal suchas man.

According to a further aspect of the present invention there is providedthe use of a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the treatment of a disease ormedical condition (for example a cancer as mentioned herein) mediatedalone or in part by erb-B, particularly erbB2, receptor tyrosine kinase.

According to a further feature of this aspect of the invention there isprovided a method for treating a disease or medical condition (forexample a cancer as mentioned herein) mediated alone or in part byerb-B, particularly erbB2, receptor tyrosine kinase in a warm-bloodedanimal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a quinazolinederivative of the formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a disease ormedical condition (for example a cancer as mentioned herein) mediatedalone or in part by erb-B, particularly erbB2, receptor tyrosine kinase.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofthose tumours which are sensitive to inhibition of erbB2 receptortyrosine kinase that is involved in the signal transduction steps whichlead to the proliferation of tumour cells.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of those tumours whichare sensitive to inhibition of erbB2 receptor tyrosine kinase, that isinvolved in the signal transduction steps which lead to theproliferation and/or survival of tumour cells in a warm-blooded animal,such as man, in need of such treatment, which comprises administering tosaid animal an effective amount of a quinazoline derivative of theformula I, or a pharmaceutically-acceptable salt thereof, as definedhereinbefore.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in the prevention or treatment of thosetumours which are sensitive to inhibition of the erbB2 receptor tyrosinekinase, that is involved in the signal transduction steps which lead tothe proliferation and/or survival of tumour cells. According to afurther aspect of the invention there is provided the use of aquinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in providing a erbB2 receptortyrosine kinase inhibitory effect.

According to a further feature of this aspect of the invention there isprovided a method for providing an erbB2 receptor tyrosine kinaseinhibitory effect in a warm-blooded animal, such as man, in need of suchtreatment, which comprises administering to said animal an effectiveamount of a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in providing an erbB2 receptor tyrosinekinase inhibitory effect.

According to a further aspect of the invention there is provided the useof a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in providing a selective erbB2kinase inhibitory effect.

According to a further feature of this aspect of the invention there isprovided a method for providing a selective erbB2 kinase inhibitoryeffect in a warm-blooded animal, such as man, in need of such treatment,which comprises administering to said animal an effective amount of aquinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in providing a selective erbB2 kinaseinhibitory effect.

By “a selective erbB2 kinase inhibitory effect” is meant that thequinazoline derivative of Formula I is more potent against erbB2receptor tyrosine kinase than it is against other kinases. In particularsome of the compounds according to the invention are more potent againsterbB2 receptor kinase than it is against other tyrosine kinases such asother erb-B receptor tyrosine kinases, particularly EGFR tyrosinekinase. For example a selective erb-B2 kinase inhibitor according to theinvention is at least 5 times, preferably at least 10 times more potentagainst erbB2 receptor tyrosine kinase than it is against EGFR tyrosinekinase, as determined from the relative IC₅₀ values in suitable assays(for example the by comparing the IC₅₀ value from the Clone 24phospho-erbB2 cell assay (a measure of the erb-B2 tyrosine kinaseinhibitory activity in cells) with the IC₅₀ from the KB cell assay (ameasure of the EGFR tyrosine kinase inhibitory activity in cells) for agiven test compound as described above).

According to a further aspect of the present invention there is providedthe use of a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the treatment of a cancer, forexample a cancer selected from leukaemia, multiple myeloma, lymphoma,bile duct, bone, bladder, brain/CNS, breast, colorectal, cervical,endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal,oesophageal, ovarian, pancreatic, pleural/peritoneal membranes,prostate, renal, skin, testicular, thyroid, uterine and vulval cancer.

According to a further feature of this aspect of the invention there isprovided a method for treating a cancer, for example a cancer selectedfrom selected from leukaemia, multiple myeloma, lymphoma, bile duct,bone, bladder, brain/CNS, breast, colorectal, cervical, endometrial,gastric, head and neck, hepatic, lung, muscle, neuronal, oesophageal,ovarian, pancreatic, pleural/peritoneal membranes, prostate, renal,skin, testicular, thyroid, uterine and vulval cancer in a warm-bloodedanimal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a quinazolinederivative of the formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a cancer, forexample a cancer selected from leukaemia, multiple myeloma, lymphoma,bile duct, bone, bladder, brain/CNS, breast, colorectal, cervical,endometrial, gastric, head and neck, hepatic, lung, muscle, neuronal,oesophageal, ovarian, pancreatic, pleural/peritoneal membranes,prostate, renal, skin, testicular, thyroid, uterine and vulval cancer.

The anti-proliferative treatment defined hereinbefore may be applied asa sole therapy or may involve, in addition to the quinazoline derivativeof the invention, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumour agents:

As mentioned above the size of the dose required for the therapeutic orprophlyactic treatment of a particular disease will necessarily bevaried depending upon, amongst other things, the host treated, the routeof administration and the severity of the illness being treated.

The anti-proliferative treatment defined hereinbefore may be applied asa sole therapy or may involve, in addition to the quinazoline derivativeof the invention, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumour agents:—

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulfan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea;antitumour antibiotics (for example anthracyclines like adriamycin,bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere); and topoisomerase inhibitors (forexample epipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbB2 antibody trastuzumab [Herceptin™] and theanti-erbB1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample other inhibitors of the epidermal growth factor family (forexample EGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD 1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in International Patent ApplicationsWO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compoundsthat work by other mechanisms (for example linomide, inhibitors ofintegrin αvβ3 function and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO00/40529,WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided apharmaceutical product comprising a quinazoline derivative of theFormula I as defined hereinbefore and an additional anti-tumour agent asdefined hereinbefore for the conjoint treatment of cancer.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of theerbB receptor tyrosine protein kinases. Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

The invention will now be illustrated by the following non limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;

(ii) organic solutions were dried over anhydrous magnesium sulfate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperatureof up to 60° C.;

(iii) chromatography means flash chromatography on silica gel; thinlayer chromatography (TLC) was carried out on silica gel plates;

(iv) in general, the course of reactions was followed by TLC and/oranalytical LC-MS, and reaction times are given for illustration only;

(v) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra and/or mass spectral data;

(vi) yields are given for illustration only and are not necessarilythose which can be obtained by diligent process development;preparations were repeated if more material was required;

(vii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHzusing perdeuterio dimethyl sulfoxide (DMSO-d₆) as solvent unlessotherwise indicated; the following abbreviations have been used: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;

(viii) chemical symbols have their usual meanings; SI units and symbolsare used;

(ix) solvent ratios are given in volume:volume (v/v) terms; and

(x) mass spectra were run with an electron energy of 70 electron voltsin the chemical ionization (CI) mode using a direct exposure probe;where indicated ionization was effected by electron impact (EI), fastatom bombardment (FAB) or electrospray (ESP); values for m/z are given;generally, only ions which indicate the parent mass are reported; andunless otherwise stated, the mass ion quoted is (MH)⁺ which refers tothe protonated mass ion; reference to M⁺ is to the mass ion generated byloss of an electron; and reference to M-H⁺ is to the mass ion generatedby loss of a proton;

(xi) unless stated otherwise compounds containing an asymmetricallysubstituted carbon and/or sulfur atom have not been resolved,

(xii) where a synthesis is described as being analogous to thatdescribed in a previous example the amounts used are the millimolarratio equivalents to those used in the previous example;

(xiii) all microwave reactions were carried out in a CEM Discover™microwave synthesisor;

(xiv) preparative high performance liquid chromatography (HPLC) wasperformed on a Gilson instrument using the following conditions: Column:21 mm × 10 cm Hichrom RPB Solvent A: Water + 0.1% trifluoroacetic acid,Solvent B: Acetonitrile + 0.1% trifluoroacetic acid Flow rate: 18 ml/minRun time: 15 minutes with a 10 minute gradient from 5-95% B Wavelength:254 nm, bandwidth 10 nm Injection volume 2.0-4.0 ml;(xv) the following abbreviations have been used:

-   -   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium        Hexafluoro-Phosphate; and    -   THF tetrahydrofuran;    -   DMF N,N-dimethylformamide;    -   DMA N,N-dimethylacetamide;    -   DCM dichloromethane;    -   DMSO dimethylsulfoxide;    -   IPA Isopropyl alcohol;    -   ether diethyl ether;    -   TFA trifluoroacetic acid.

EXAMPLE 12-((2R)-2-{[(4-{[3-Chloro-4-pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

A mixture of HATU (69 mg), diisopropylethylamine (58 μl), glycolic acid(13 mg) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(70 mg) in DCM (5 ml) was stirred overnight. The solution wasconcentrated in vacuo and the residue purified by chromatography usingDCM—5% methanol as eluent to give the title compound as a white solid(48 mg, 61%); NMR spectrum (DMSO-d6) 1.85-2.10 (m, 4H), 3.42 (m, 2H),4.04 (m, 2H), 4.20 (dd, 1H), 4.45 (dd, 1H), 4.52 (t, 1H), 4.60 (m, 1H),5.30 (s, 2H), 7.25 (d, 2H), 7.38 (m, 2H), 7.58 (m, 2H), 7.73 (t, 1H),7.89 (t, 1H), 8.05 (d, 1H), 8.48 (s, 1H), 8.60 (d, 1H), 9.98 (bs, 1H);Mass spectrum MH⁺ 520.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amineused as starting material was prepared as follows:

DMF (0.2 ml) was added to a suspension of5-fluoro-3,4-dihydro-3H-quinazolin-4-one (1.64 g) in thionyl chloride(10 ml) and the mixture was stirred and heated at 80° C. for 6 hours.Volatile material was removed by evaporation and the residue wasazeotroped with toluene (20 ml). The resulting solid was addedportionwise to a vigorously stirred mixture of saturated sodiumbicarbonate (50 ml), crushed ice (50 g) and DCM (50 ml) such that thetemperature was kept below 5° C. The organic phase was separated, driedand concentrated to give 4-chloro-5-fluoroquinazoline (1.82 g, 99%) as asolid which was used without purification; NMR spectrum (CDCl₃)7.35-7.45 (m, 1H), 7.85-7.95 (m, 2H), 9.0 (s, 1H).

4-Chloro-5-fluoroquinazoline (6.75 g) was added to stirred solution of3-chloro-4-(2-pyridylmethoxy)aniline (9.27 g, obtained as described inExample 13 of WO 96/15118) in IPA (200 ml), and the solution was stirredand heated at reflux for 8 hours. The solution was allowed to cool toambient temperature overnight and the precipitated solid was filteredoff, washed with acetone and dried. The solid was added to 50% aqueousmethanol (400 ml) and the mixture was heated on a steam bath until allthe solid had dissolved. The solution was basified by careful additionof aqueous ammonia (0.880), and the mixture was concentrated to removemethanol. Water (300 ml) was added and the mixture was extracted withDCM (600 ml). The extract was washed with water, and brine, and dried.The solvent was removed by evaporation to give a solid, which wasre-precipitated from a mixture of ethyl acetate, tetrahydrofuran andisohexane to giveN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine asa beige solid (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7.3(d, 1H), 7.35-7.5 (m, 2H), 7.5-7.65 (m, 3H), 7.8-7.95 (m, 3H), 8.55 (s,1H), 8.55-8.6 (d, 1H), 9.1-9.2 (bs, 1H); Mass spectrum MH³⁰ 381.

Sodium hydride (60% dispersion in mineral oil, 0.16 g) was added toR-prolinol (0.39 ml) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(0.5 g) in DMA (4 ml) and the reaction heated at 95° C. for 4 hours. Thereaction was cooled, quenched with water, and concentrated in vacuo. Theresidue was purified by chromatography using DCM—5% methanol/7N ammoniaas eluent to giveN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amineas a beige solid (0.27 g, 45%); NMR spectrum (DMSO-d6) 1.47 (m, 1H),1.69 (m, 2H), 1.86 (m, 1H), 2.85 (m, 2H), 3.53 (m, 1H), 4.05 (dt, 1H),4.31 (dd, 1H), 5.27 (s, 2H), 7.12 (d, 1H), 7.23 (d, 1H), 7.31 (d, 1H),7.35 (dd, 1H), 7.57 (d, 1H), 7.70 (t, 1H), 7.79 (dd, 1H), 7.86 (dt, 1H),8.14 (d, 1H), 8.50 (s, 1H), 8.58 (d, 1H), 10.55 (bs, 1H); Mass spectrumM⁺ 462.

EXAMPLE 22-((2S)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(25)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminein 75% yield; NMR spectrum (DMSO-d6) 1.98 (m, 4H), 3.40 (m, 2H), 4.02(m, 2H), 4.18 (dd, 1H), 4.43 (dd, 1H), 4.52 (m, 1H), 5.26 (s, 2H), 7.23(d, 2H), 7.34 (m, 2H), 7.57 (d, 2H), 7.71 (t, 1H), 7.86 (d, 1H), 8.02(d, 1H), 8.46 (s, 1H), 8.59 (d, 1H), 9.95 (bs, 1H); Mass spectrum MH⁺520.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amineused as starting material was prepared as described in example 1(preparation of starting materials) using S-prolinol andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine in51% yield; NMR spectrum (DMSO-d6) 1.47 (m, 1H), 1.69 (m, 2H), 1.86 (m,1H), 2.85 (m, 2H), 3.53 (m, 1H), 4.05 (dt, 1H), 4.31 (dd, 1H), 5.27 (s,2H), 7.12 (d, 1H), 7.23 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H), 7.57 (d,1H), 7.70 (t, 1H), 7.79 (dd, 1H), 7.86 (dt, 1H), 8.14 (d, 1H), 8.50 (s,1H), 8.58 (d, 1H), 10.55 (bs, 1H); Mass spectrum M⁺ 462.

EXAMPLE 3N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(obtained as described in example 1, preparation of starting materials)in 84% yield; Mass spectrum M⁺ 547.

EXAMPLE 4N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(obtained as described in example 2, preparation of starting materials)in 86% yield; Mass spectrum M⁺ 547.

EXAMPLE 52-((3S)-3-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-morpholin-3-ylmethoxy]quinazolin-4-aminein 40% yield; NMR spectrum (DMSO-d6) 3.5 (m, 2H), 3.6 (m, 1H), 3.8 (m,1H), 3.9-4.2 (m, 4H), 4.5 (m, 2H), 4.6 (t, 1H), 4.8 (m, 1H), 5.3 (s,2H), 7.2 (d, 2H), 7.4 (m, 2H), 7.5 (d, 1H), 7.6 (d, 1H), 7.7 (t, 1H),7.9 (m, 2H), 8.4 (s, 1H), 8.6 (d, 1H), 9.7 (bs, 1H); Mass spectrum M⁺536.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-morpholin-3-ylmethoxy]quinazolin-4-amineused as starting material was prepared as described in example 1(preparation of starting materials) using (3R)-morpholin-3-ylmethanol(obtained as described in J. Chem. Soc. Perkin Trans. 1, 2577-2580(1985)) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine in53% yield; NMR spectrum (DMSO-d6) 2.90 (3H, m+bs), 3.23 (m, 1H), 3.34(m, 2H), 3.68 (dd, 1H), 3.80 (dd, 1H), 4.22 (m, 2H), 5.28 (s, 2H), 7.08(d, 1H), 7.28 (t, 1H), 7.34 (m, 2H), 7.57 (d, 1H), 7.71 (t, 1H), 7.83(m, 2H), 8.08 (d, 1H), 8.50 (s, 1H), 8.58 (d, 1H), 10.53 (bs, 1H); Massspectrum M⁺ 478.

EXAMPLE 6N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-4-[(dimethylamino)acetyl]morpholin-3-yl}methoxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-morpholin-3-ylmethoxy]quinazolin-4-amine(obtained as described in example 5, preparation of starting materials)in 77% yield; Mass spectrum M⁺ 563.

EXAMPLE 72-((2R)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-aminein 51% yield; NMR spectrum (DMSO-d6) 1.49 (m, 1H), 1.60-1.77 (m, 4H),1.88 (m, H), 3.14 (t, 1H), 3.79 (m, 1H), 3.96-4.18 (m, 3H), 4.45 (dd,1H), 4.65 (t, 1H), 4.93 (bs, 1H), 5.28 (s, 2H), 7.24 (m, 2H), 7.32 (dd,1H), 7.38 (d, 1H), 7.55 (dd, 1H), 7.58 (d, 1H), 7.72 (t, 1H), 7.83 (t,1H), 7.94 (d, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.60 (s, 1H); Massspectrum M⁺ 534.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-amineused as starting material was prepared as described in example 1(preparation of starting materials) usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amineand (2R)-piperidin-2-ylmethanol in 33% yield; NMR spectrum (DMSO-d6)1.30-1.39 (m, 2H), 1.56 (m, 1H), 1.57 (m, 1H), 1.69 (dd, 1H), 1.82 (m,1H), 2.67 (m, 1H), 3.02 (m, 1H), 3.08 (m, 1H), 4.15 (dd, 1H), 4.27 (dd,1H), 5.27 (s, 2H), 7.09 (d, 1H), 7.24 (d, 1H), 7.31 (m, 2H), 7.56 (d,1H), 7.66 (t, 1H), 7.85 (m, 2H), 8.07 (d, 1H), 8.49 (s, 1H), 8.57 (d,1H), 10.42 (bs, 1H); Mass spectrum M⁺ 477.

The (2R)-piperidin-2-ylmethanol used as starting material was preparedas follows: Trifluoroacetic acid (3 ml) was carefully added to astirring solution oftert-butyl(2R)-2-(hydroxymethyl)piperidine-1-carboxylate (1.15 g,obtained as described in Tetrahedron, 58 (2002), 1343-1354) in DCM (3ml) and stirred at room temperature for 1 hour. Volatiles were removedin vacuo and the oil thus obtained dissolved in methanol (60 ml), andneutralized by addition of MP-Carbonate resin (polymer supportedcarbonate reagent ex. Argonaut Technologies Inc.) (approximately 1 g)whilst stirring at room temperature for 2 hours. The resin was filtered,washed with methanol (3×30 ml) and the filtrate concentrated. Theresulting oil was dissolved in DCM (30 ml) and dried (MgSO₄) beforefiltration and solvent removal to afford a grey oil (615 mg, 100%); NMRspectrum (DMSO-d6) 1.44-1.51 (m, 2H), 1.61 (m, 1H), 1.70-1.78 (m, 3H),2.84 (m, 1H), 3.03 (m, 1H), 3.21 (d, 1H), 3.49 (m, 1H), 3.57 (dd, 1H),5.01 (bs, 1H), 7.65 (bs, 1H); Mass spectrum M⁺ 116.

EXAMPLE 82-((2S)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(25)-piperidin-2-ylmethoxy]quinazolin-4-aminein 50% yield; NMR spectrum (DMSO-d6) 1.48 (m, 1H), 1.62-1.75 (m, 4H),1.90 (m, 1H), 3.15 (t, 1H), 3.78 (m, 1H), 3.98-4.05 (m, 3H), 4.42 (dd,1H), 4.65 (t, 1H), 4.95 (bs, 1H), 5.29 (s, 2H), 7.24 (t, 2H), 7.34 (dd,1H), 7.35 (t, 1H), 7.55 (dd, 1H), 7.58 (d, 1H), 7.71 (t, 1H), 7.84 (m,1H), 7.94 (d, 1H), 8.45 (s, 1H), 8.57 (d, 1H), 9.62 (s, 1H); Massspectrum M⁺ 535.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-amineused as starting material was prepared as described in example 1preparation of starting materials) usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amineand (2S)-piperidin-2-ylmethanol in 24% yield; NMR spectrum (DMSO-d6)1.29-1.48 (m, 3H), 1.55 (d, 1H), 1.62 (d, 1H), 1.83 (d, 1H), 2.67 (t,1H), 2.99 (m, 1H), 3.09 (d, 1H), 4.14 (dd, 1H), 4.27 (dd, 1H), 5.29 (s,2H), 7.09 (d, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.38 (dd, 1H), 7.58 (d,1H), 7.72 (t, 1H), 7.86 (t, H), 7.95 (dd, 1H), 8.09 (d, 1H), 8.52 (s,1H), 8.59 (d, 1H), 10.61 (s, 1H); Mass spectrum M⁺ 476.

The (2S)-piperidin-2-ylmethanol used as starting material was obtainedas described in example 7 (preparation of starting materials) usingtert-butyl(2S)-2-(hydroxymethyl)piperidine-1-carboxylate (obtained asdescribed in Tetrahedron, 58 (2002), 1343-1354) in 100% yield; NMRspectrum (DMSO-d6) 1.44-1.51 (m, 2H), 1.61 (m, 1H), 1.70-1.79 (m, 3H),2.86 (m, 1H), 3.06 (m, 1H), 3.23 (d, 1H), 3.48 (m, 1H), 3.58 (dd, 1H),5.01 (bs, 1H), 7.80 (bs, 1H); Mass spectrum M⁺ 116.

EXAMPLE 9N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-amine(obtained as described in example 7, preparation of starting materials)in 39% yield; NMR spectrum (DMSO-d6) 1.45 (m, 1H), 1.61-1.75 (m, 4H),1.89 (m, 1H), 2.10 (s, 6H), 2.98 (s, 2H), 3.14 (t, 1H), 4.11 (d, 1H),4.44 (t, 1H), 4.68 (t, 1H), 5.05 (bs, 1H), 5.27 (s, 2H), 7.22 (t, 2H),7.28 (d, 1H), 7.30 (d, 1H), 7.56 (dd, 2H), 7.72 (t, 1H), 7.85 (t, 1H),7.94 (d, 1H), 8.43 (s, 1H), 8.59 (d, 1H), 9.66 (s, 1H); Mass spectrum M⁺562.

EXAMPLE 10N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-amine(obtained as described in example 8, preparation of starting materials)in 64% yield; NMR spectrum (DMSO-d6) 1.48 (m, 1H), 1.61-1.73 (m, 4H),1.87 (m, 1H), 2.12 (s, 6H), 3.08-3.18 (m, 3H), 4.03 (m, 1H), 4.45 (m,1H), 4.67 (m, 1H), 5.05 (bs, 1H), 5.27 (s, 2H), 7.25 (t, 2H), 7.33 (d,1H), 7.35 (t, 1H), 7.58 (dd, 2H), 7.72 (t, 1H), 7.84 (t, 1H), 7.96 (d,1H), 8.45 (s, 1H), 8.5 (d, 1H), 9.65 (s, 1H); Mass spectrum M⁺ 562.

EXAMPLE 111-((2R)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ol

The procedure described in example 1 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amineand 2-methyllactic acid in 40% yield; NMR spectrum (DMSO-d6) 1.29 (s,6H), 1.88 (m, 2H), 1.99 (m, 2H), 3.67 (m, 1H), 4.02 (m, 1H), 4.20 (m,1H), 4.42 (m, 1H), 4.64 (bs, 1H), 5.19 (s, 1H), 5.30 (s, 2H), 7.28 (d,2H), 7.33 (d, 1H), 7.38 (dd, 1H), 7.58 (m, 2H), 7.73 (t, 1H), 7.89 (t,1H), 8.0 (s, 1H), 8.47 (s, 1H), 8.59 (d, 1H), 9.98 (s, 1H); Massspectrum M⁺ 549.

EXAMPLE 121-[((2R)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)carbonyl]cyclopropanol

The procedure described in example 1 was repeated using1-hydroxy-1-cyclopropanecarboxylic acid andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminein 41% yield; NMR spectrum (DMSO-d6) 0.70 (m, 1H), 0.82 (m, 2H), 1.06(m, 1H), 1.88 (m, 2H), 2.05 (m, 2H), 3.76 (m, 1H), 3.91 (m, 1H), 4.22(m, 1H), 4.40 (m, 1H) 4.61 (m, 1H), 5.32 (s, 2H), 6.14 (s, 1H), 7.22 (t,2H), 7.34 (m, 2H), 7.53 (dd, 1H), 7.56 (d, 1H), 7.73 (t, 1H), 7.88 (t,1H), 7.97 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.97 (s, 1H); Massspectrum M⁺ 547.

EXAMPLE 133-((2R)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol

The procedure described in example 1 was repeated using2,2-dimethyl-3-hydroxypropionic acid andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminein 56% yield; NMR spectrum (DMSO-d6) 1.11 (s, 6H), 1.89 (m, 2H), 2.02(m, 2H), 3.42 (m, 2H), 3.58 (m, 1H), 3.75 (m, 1H), 4.18 (m, 1H), 4.45(dd, 1H), 4.58 (t, 1H), 4.64 (m, 1H), 5.31 (s, 2H), 7.26 (dd, 2H), 7.32(dd, 1H), 7.38 (m, 1H), 7.58 (m, 2H), 7.72 (t, 1H), 7.89 (m, 1H), 8.06(d, 1H), 8.48 (s, 1H), 8.61 (d, 1H), 9.96 (s, 1H); Mass spectrum M⁺ 562.

EXAMPLE 14(2S)-1-((2R)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol

The procedure described in example 1 was repeated using L-lactic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminein 60% yield; NMR spectrum (DMSO-d6) 1.13 (d, 3H), 1.91 (m, 2H), 2.03(m, 2H), 3.58 (m, 2H), 3.66 (m, 1H), 4.28 (m, 2H), 4.45 (m, 1H), 4.59(m, 1H), 5.33 (s, 2H), 7.33 (t, 1H), 7.38 (s, 1H), 7.39 (dd, 1H),7.51-7.62 (m, 3H), 7.86 (d, 1H), 7.91 (m, 1H), 8.0 (t, 1H), 8.61 (d,1H), 8.79 (s, 1H), 11.12 (s, 1H); Mass spectrum M⁺ 534.

EXAMPLE 15N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(ethoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine

The procedure described in example 1 was repeated using ethoxyaceticacid andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminein 49% yield; NMR spectrum (DMSO-d6) 1.05 (t, 3H), 1.92 (m, 2H), 2.05(m, 2H), 3.44 (q, 2H), 3.73 (m, 2H), 4.01 (s, 2H), 4.32 (dd, 1H), 4.53(dd, 1H), 4.64 (m, 1H), 5.31 (s, 2H), 7.31 (d, 1H), 7.38 (dd, 1H), 7.45(d, 1H), 7.51 (d, 1H), 7.57 (dd, 1H), 7.62 (d, 1H), 7.83 (s, 1H), 7.90(m, 1H), 7.95 (t, 1H), 8.60 (d, 1H), 8.69 (d, 1H), 10.92 (bs, 1H); Massspectrum M⁺ 549.

EXAMPLE 16N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine

The procedure described in example 1 was repeated using methoxyaceticacid andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminein 36% yield; NMR spectrum (DMSO-d6) 1.92 (m, 2H), 2.05 (m, 2H), 3.25(s, 3H), 4.0 (d, 2H), 4.35 (dd, 1H), 4.49 (dd, 1H), 4.63 (m, 1H), 5.36(s, 2H), 7.32 (d, 1H), 7.38 (dd, 1), 7.43 (d, 1H), 7.47 (d, 1H), 7.57(m, 2H), 7.85 (s, 1H), 7.88 (t, 1H), 7.96 (t, 1H), 8.59 (d, 1H), 8.73(s, 1H), 10.94 (bs, 1H); Mass spectrum M⁺ 535.

EXAMPLE 172-{(3S)-3-[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-pyrrolidin-3-yloxy]quinazolin-4-aminein 45% yield; NMR spectrum (DMSO-d6) 2.35-2.45 (bs, 2H), 3.57-3.67 (m,1H), 3.7-3.8 (m, 1H), 3.8-4.0 (m, 2H), 4.0-4.1 (m, 2H), 4.2-4.3 (bs,1H), 5.3 (s, 1H), 5.4-5.5 (bs, 1H), 7.2-7.3 (dd, 2H), 7.3-7.4 (m, 1H),7.4-7.5 (m, 2H), 7.6-7.65 (d, 1H), 7.7-7.8 (t, 1H), 7.8-7.9 (m, 1H), 8.1(s, 1H), 8.5 (s, 1H), 8.6 (d, 1H), 9.7 (bs, 1H); Mass spectrum MH⁺ 507.

TheN-[3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-5-[(3S)-pyrrolidin-3-yloxy]quinazolin-4-amineused as starting material was prepared as follows:

Sodium hydride (60% dispersion in oil, 220 mg) was added to a solutionof N-tert-butoxycarbonyl-(3S)-hydroxypyrrolidine (1.02 g), 15-crown-5(10 mg) andN-[3-chloro-4-pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(0.95 g, obtained as described in example 1, preparation of startingmaterials) in 1,4-dioxane (40 ml) and heated at 150° C. for 20 minutesin a sealed vessel using a microwave synthesisor. The solution wascooled and pH adjusted to 7 by addition of glacial acetic acid and thenconcentrated in vacuo. The residue was purified by chromatography onsilica using ethyl acetate—5% methanol as eluent to givetert-butyl(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidine-1-carboxylate(1.6 g) as an oil; Mass spectrum MH⁺ 548.

tert-Butyl(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidine-1-carboxylate(1.6 g) was dissolved in trifluoroacetic acid (50 ml) and stood atambient temperature for 17 hours. The solution was concentrated in vacuoand the residue dissolved in water (100 ml) and pH adjusted to 8 byaddition of 880 ammonia solution. The precipitate was extracted into hotethyl acetate and washed with water, dried (MgSO₄) and evaporated togiveN-[3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-5-[(3S-pyrrolidin-3-yloxy]-quinazolin-4-amine(0.52 g, 46%); NMR spectrum (DMSO-d6) 1.9-2.1 (bs, 1H), 2.15-2.25 (m,1H), 2.9-3.3 (m, 3H), 5.25 (s, 2H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3-7.4(m, 2H), 7.5-7.65 (m, 2H), 7.8-7.85 (t, 1H), 8.1-8.2 (bs, 1H), 8.5 (s,1H), 8.55 (d, 1H), 10.0-10.1 (bs, 1H); Mass spectra MH⁺ 448.

EXAMPLE 18N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}oxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-5-[(3S)-pyrrolidin-3-yloxy]quinazolin-4-amine(obtained as described in example 17, preparation of starting materials)in 29% yield; NMR spectrum (DMSO-d6) 2.2 (s, 6H), 2.3-2.5 (bs, 2H), 3.0(s, 2H), 3.4-3.9 (bs, 2H), 3.9-4.2 (bs, 2H), 5.3 (s, 1H), 5.4-5.5 (bs,1H), 7.2-7.3 (t, 2H), 7.3-7.4 (m, 1H), 7.4-7.45 (d, 1H), 7.45-7.5 (dd,1H), 7.6-7.65 (d, 1H), 7.7-7.8 (t, 1H), 7.8-7.9 (t, 1H), 8.0-8.1 (bs,1H), 8.5 (s, 1H), 8.6 (s, 1H), 9.7-9.8 (bs, 1H); Mass spectrum MH⁺ 534.

EXAMPLE 192-{(3R)-3-[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-5-[(3R)-pyrrolidin-3-yloxy]quinazolin-4-aminein 25% yield, NMR spectrum (DMSO-d6) 2.35-2.45 (bs, 2H), 3.57-3.67 (m,1H), 3.7-3.8 (m, 1H), 3.8-4.0 (m, 2H), 4.0-4.1 (m, 2H), 4.2-4.3 (bs,1H), 5.3 (s, 1H), 5.4-5.5 (bs, 1H), 7.2-7.3 (dd, 2H), 7.3-7.4 (m, 1H),7.4-7.5 (m, 2H), 7.6-7.65 (d, 1H), 7.7-7.8 (t, 1H), 7.8-7.9 (m, 1H), 8.1(s, 1H), 8.5 (s, 1H), 8.6 (d, 1H), 9.7 (bs, 1H); Mass spectrum MH⁺ 507.

TheN-[3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-5-[(3R)-pyrrolidin-3-yloxy]quinazolin-4-amineused as starting material was prepared as described in example 17(preparation of starting materials) usingN-tert-butoxycarbonyl-(3R)-hydroxypyrrolidine andN-[3-chloro-4-pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine in98% yield; NMR spectrum (CDCl₃) 1.6-1.9 (bs, 2H), 2.1 2.3 (m, 1H),2.3-2.5 (m, 1H), 3.2-3.6 (m, 2H), 5.2-5.3 (bs, 1H), 5.4 (s, 1H), 6.9-7.0(d, 1H), 7.05-7.15 (d, 1H), 7.15-7.2 (m, 1H), 7.5-7.6 (d, 1H), 7.6-7.7(dd, 1H), 7.7-7.8 (m, 2H), 7.8-7.9 (dt, 1H), 8.15 (d, 1H), 8.7-8.75 (d,1H), 8.75 (s, 1H), 10.1 (bs, 1H); Mass spectrum MH⁺ 448.

EXAMPLE 20N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}quinazolin-4-amine

The procedure described in example 1 was repeated using methoxyaceticacid andN-[3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-5-[(3R)-pyrrolidin-3-yloxy]quinazolin-4-amine(obtained as described in example 19, preparation of starting materials)to give the title compound in 33% yield; NMR spectrum (DMSO-d6) 2.3-2.5(bs, 2H), 3.2 (s, 3H), 3.5-3.7 (m, 2H), 3.7-4.1 (m, 4H), 5.25 (s, 2H),5.4-5.5 (bs, 1H), 7.2-7.25 (d, 2H), 7.3-7.35 (m, 1H), 7.35-7.4 (d, 1H),7.4-7.5 (dd, 1H), 7.55-7.6 (d, 1H), 7.7-7.8 (t, 1H), 7.8-7.9 (t, 1H),8.0 (s, 1H), 8.55 (s, 1H), 8.55-8.65 (d, 1H), 9.6-9.8 (bs, 1H); Massspectrum MH⁺ 521.

EXAMPLE 21N-[3-Chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

A mixture of2-chloro-4-[(5-{[(2R)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(70 mg), potassium carbonate (138 mg) and 18-crown-6 (10 mg) in DMA (5ml) was stirred and sonicated for 5 minutes. 4-(chloromethyl)thiazolehydrochloride (29 mg) was added, and the mixture was stirred at roomtemperature for 16 hours. The mixture was concentrated in vacuo, and theresidue partitioned between DCM (15 ml) and water (15 ml). The DCMfraction was purified by chromatography using 2-5% of 10:1methanol/aqueous ammonia (0.880) in DCM as eluent. The appropriatefractions were evaporated, and the residue was triturated with diethylether to give the title product as a white solid (24 mg, 28%); NMRspectrum (DMSO-d6) 1.85-2.10 (m, 4H), 2.19 (s, 6H), 2.99 (d, 1H), 3.11(d, 1H), 3.56 (m, 2H), 4.21 (dd, 1H), 4.41 (dd, 1H), 4.60 (m, 1H), 5.35(s, 2H), 7.22 (d, 1H), 7.32 (d, 1H), 7.33 (d, 1H), 7.60 (dd, 1H), 7.72(dd, 1H), 7.81 (s, 1H), 8.00 (d, 1H), 8.47 (s, 1H), 9.15 (s, 1H), 9.98(s, 1H); Mass spectrum MH⁺ 554.

The2-chloro-4-[(5-{[(2R)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as follows:

4-Amino-2-chlorophenol (8.65 g) was dissolved in iso-propanol (200 ml)and 4-chloro-5-fluoroquinazoline (prepared as described in example 1,preparation of starting materials, 10.00 g) was added. The mixture washeated under reflux for 2 hours, causing a yellow solid to precipitate.The mixture was cooled to ambient temperature; the solid was collectedby filtration and washed with cold isopropanol (100 ml). The solid wasdissolved in a boiling mixture of methanol (550 ml) and water (100 ml).With vigorous stirring, the solution was basified with aqueous ammonia(0.880, 20 ml), causing a pale pink solid to precipitate. The mixturewas concentrated in vacuo to such a volume that all of the methanol hadbeen removed, leaving the product as a suspension in aqueous solution.The suspension was cooled; the solid was collected by filtration,triturated with ethyl acetate and dried to give2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol as a pale pink solid(13.5 g, 85%); NMR spectrum (DMSO-d6) 6.97 (d, 1H), 7.38 (dd, 1H), 7.42(dd, 1H), 7.59 (d, 1H), 7.73 (d, 1H), 7.81 (ddd, 1H), 8.51 (s, 1H), 9.03(d, 1H), 10.07 (bs, 1H); Mass spectrum MH⁺ 290.

Sodium hydride (60% dispersion in mineral oil, 1.50 g) was suspended inDMA (100 ml), and D-prolinol (3.70 ml) was added dropwise under anitrogen atmosphere. The mixture was stirred for 30 minutes at ambienttemperature, and the 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol(4.34 g) was added. The mixture was heated to 110° C. for 2 hours undera nitrogen atmosphere, and then cooled to ambient temperature. Saturatedammonium chloride solution (15 ml) was added, and the mixtureconcentrated in vacuo. The residue was treated with saturated sodiumhydrogen carbonate solution (150 ml), and the mixture stirred andsonicated to give a granular precipitate. The solid was collected byfiltration, triturated with ethyl acetate, and dried to give2-chloro-4-({5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolas a cream coloured solid (4.72 g, 85%); NMR spectrum (DMSO-d6) 1.50 (m,1H), 1.60-1.77 (m, 2H), 1.88 (m, 1H), 2.80-2.95 (m, 2H), 3.57 (m, 1H),4.07 (dd, 1H), 4.32 (dd, 1H), 6.99 (d, 1H), 7.12 (d, 1H), 7.31 (d, 1H),7.62 (dd, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.49 (s, 1H), 10.50 (bs,1H); Mass spectrum MH⁺ 371.

HATU (1.14 g) was added to a mixture of the2-chloro-4-({5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenol(1.11 g) and N,N-dimethylglycine (340 mg) in DMF (70 ml). The mixturewas stirred at ambient temperature for 16 hours, and then concentratedin vacuo. The residue was treated with water to give a pale yellow solidthat was collected by filtration, and washed with water. The solid wastreated with a mixture of DCM (10 ml), methanol (10 ml) and aqueousammonia (0.880, 1 ml), and the mixture stirred and sonicated for 10minutes. The resulting white solid was collected by filtration to give2-chloro-4-[(5-{[(2R)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolas a white solid (600 mg, 44%); NMR spectrum (DMSO-d6) 1.90-2.15 (m,4H), 3.47 (m, 2H), 3.88 (s, 2H), 4.25 (dd, 1H), 4.47 (dd, 1H), 4.60 (m,1H), 7.00 (d, 1H), 7.24 (d, 1H), 7.34 (d, 1H), 7.44 (dd, 1H), 7.72 (dd,1H), 7.90 (d, 1H), 8.47 (s, 1H), 9.88 (s, 1H), 10.04 (s, 1H); Massspectrum MH⁺ 457.

EXAMPLE 222-((2R)-2-{[(4-{[3-Chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using2-chloro-4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenoland 4-(chloromethyl)thiazole hydrochloride in 50% yield; NMR spectrum(DMSO-d₆) 1.90-2.10 (m, 4H), 3.40 (m, 2H), 4.05 (m, 2H), 4.21 (dd, 1H),4.47 (dd, 1H), 4.53 (t, 1H), 4.60 (m, 1H), 5.35 (s, 2H), 7.27 (d, 1H),7.34 (d, 1H), 7.35 (d, 1H), 7.60 (dd, 1H), 7.72 (dd, 1H), 7.81 (s, 1H),8.02 (d, 1H), 8.49 (s, 1H), 9.16 (s, 1H), 9.98 (s, 1H); Mass spectrumMH⁺ 527.

The2-chloro-4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as described in example 21(preparation of starting materials) using glycolic acid and2-chloro-4-({5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolin 62% yield; NMR spectrum (DMSO-d6) 1.85-2.10 (m, 4H), 3.10-3.30 (m,2H), 4.05 (q, 2H), 4.30 (dd, 1H), 4.48 (dd, 1H), 4.62 (m, 1H), 7.05 (d,1H), 7.38 (d, 1H), 7.40 (dd, 1H), 7.52 (d, 1H), 7.71 (d, 1H), 7.99 (dd,1H), 8.79 (s, 1H), 10.40 (s, 1H), 11.03 (s, 1H); Mass spectrum MH⁺ 429.

EXAMPLE 23N-{3-Chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 21 was repeated using2-chloro-4-[(5-{[(2R)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenoland 3-(chloromethyl)-5-methylisoxazole in 38% yield; NMR spectrum(DMSO-d6) 1.85-2.10 (m, 4H), 2.20 (s, 6H), 2.41 (s, 3H), 3.00 (d, 1H),3.11 (d, 1H), 3.58 (m, 2H), 4.16 (dd, 1H), 4.46 (dd, 1H), 4.60 (m, 1H),5.23 (s, 2H), 6.30 (s, 1H), 7.20 (d, 1H), 7.27 (d, 1H), 7.34 (d, 1H),7.60 (dd, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.47 (s, 1H), 9.90 (s, 1H);Mass spectrum MH⁺ 552.

EXAMPLE 242-[(2R)-2-({[4-({3-Chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using2-chloro-4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 22, preparation of starting materials)and 3-(chloromethyl)-5-methylisoxazole in 28% yield; NMR spectrum(DMSO-d6) 1.90-2.10 (m, 4H), 2.45 (s, 3H), 3.41 (m, 2H), 4.04 (m, 2H),4.21 (dd, 1H), 4.47 (dd, 1H), 4.53 (t, 1H), 4.60 (m, 1H), 5.28 (s, 2H),6.37 (s, 1H), 7.26 (d, 1H), 7.30 (d, 1H), 7.35 (d, 1H), 7.60 (dd, 1H),7.72 (dd, 1H), 8.48 (s, 1H), 10.00 (s, 1H); Mass spectrum MH⁺ 525.

EXAMPLE 25N-[3-Chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

Methanesulfonyl chloride (20 μl) was added to a solution of1,3-thiazol-5-ylmethanol (26 mg) and N,N-diisopropylethylamine (44 μl)in DCM (5 ml) at 0° C. The mixture was heated to 40° C. for 6 hours, andthen concentrated in vacuo. The residue was dissolved in DMA (5 ml), andadded to a suspension of2-chloro-4-[(5-{[(2R)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(prepared as described in example 21, preparation of starting materials,68 mg), potassium carbonate (104 mg), and 18-crown-6 (10 mg) in DMA (5ml). The mixture was stirred at room temperature for 16 hours, thenconcentrated in vacuo. The residue was partitioned between DCM (15 ml)and water (15 ml). The DCM fraction was loaded onto a silica column,which was purified by chromatography using 2-5% 10:1 methanol/aqueousammonia (0.880) in DCM as eluent. The appropriate fractions wereconcentrated and the residue triturated with diethyl ether to give thetitle product as a pale yellow solid (23 mg, 28%); NMR spectrum(DMSO-d6) 1.90-2.10 (m, 4H), 2.22 (s, 6H), 3.02 (d, 1H), 3.18 (d, 1H),3.61 (m, 2H), 4.26 (dd, 1H), 4.47 (dd, 1H), 4.63 (m, 1H), 5.58 (s, 2H),7.28 (d, 1H), 7.39 (d, 1H), 7.40 (d, 1H), 7.68 (dd, 1H), 7.78 (dd, 1H),8.06 (d, 1H), 8.09 (s, 1H), 8.52 (s, 1H), 9.19 (s, 1H), 10.04 (s, 1H);Mass spectrum MH⁺ 554.

EXAMPLE 262-((2R)-2-{[(4-{[3-Chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 25 was repeated using2-chloro-4-[(5-{[(2-R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(prepared as described in example 22, preparation of starting materials)and 1,3-thiazol-5-ylmethanol in 36% yield; NMR spectrum (DMSO-d6)1.90-2.10 (m, 4H), 3.40 (m, 2H), 4.05 (m, 2H), 4.21 (dd, 1H), 4.47 (dd,1H), 4.53 (t, 1H), 4.60 (m, 1H), 5.51 (s, 2H), 7.26 (d, 1H), 7.33 (d,1H), 7.34 (d, 1H), 7.61 (dd, 1H), 7.73 (dd, 1H), 8.02 (d, 1H), 8.03 (s,1H), 8.49 (s, 1H), 9.14 (s, 1H), 10.00 (s, 1H); Mass spectrum MH⁺ 526.

EXAMPLE 27N-[3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 25 was repeated usingpyrazin-2-ylmethanol and2-chloro-4-[(5-{[(2R)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(prepared as described in example 21, preparation of starting materials)in 44% yield; NMR spectrum (DMSO-d6) 1.85-2.10 (m, 4H), 2.19 (s, 6H),3.00 (d, 1H), 3.12 (d, 1H), 3.56 (m, 2H), 4.20 (dd, 1H), 4.41 (dd, 1H),4.59 (m, 1H), 5.40 (s, 2H), 7.23 (d, 1H), 7.31 (d, 1H), 7.34 (d, 1H),7.62 (dd, 1H), 7.72 (dd, 1H), 8.03 (d, 1H), 8.48 (s, 1H), 8.67 (d, 1H),8.70 (d, 1H), 8.87 (s, 1H), 10.00 (s, 1H); Mass spectrum MH⁺ 549.

EXAMPLE 282-((2R)-2-{[(4-{[3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 25 was repeated usingpyrazin-2-ylmethanol and2-chloro-4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(prepared as described in example 22, preparation of starting materials)in 36% yield; NMR spectrum (DMSO-d6) 1.85-2.10 (m, 4H), 3.41 (m, 2H),4.05 (m, 2H), 4.21 (dd, 1H), 4.46 (dd, 1H), 4.53 (t, 1H), 4.61 (m, 1H),5.40 (s, 2H), 7.27 (d, 1H), 7.32 (d, 1H), 7.36 (d, 1H), 7.62 (dd, 1H),7.73 (dd, 1H), 8.07 (d, 1H), 8.49 (s, 1H), 8.67 (d, 1H), 8.70 (d, 1H),8.88 (s, 1H), 10.00 (s, 1H); Mass spectrum MH⁺ 522.

EXAMPLE 292-{(3S)-3-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-yloxy]quinazolin-4-aminein 36% yield; NMR spectrum (CDCl₃) 1.76-1.97 (m, 2H), 2.04-2.23 (m, 4H),3.19-3.30 (m, 1H), 3.42-3.67 (m, 1H), 3.71-3.88 (m, 1H), 3.90-4.14 (m,2H), 4.68 (s, 1H), 5.21 (s, 2H), 6.79-7.00 (m, 2H), 7.13-7.21 (m, 2H),7.40 (d, 1H), 7.52-7.62 (m, 2H), 7.64-7.73 (m, 1H), 7.75 (s, 1H),8.46-8.55 (m, 2H), 9.50 (s, 1H); Mass spectrum MH⁺ 520.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S-piperidin-3-yloxy]quinazolin-4-amineused as starting material was prepared as follows:

(S)-3-Hydroxypiperidine hydrochloride (15 g), diisopropylethylamine(20.9 ml) and 4-dimethylaminopyridine (1.33 g) were stirred in DCM (150ml) and cooled to 0° C. A solution of di-tert-butyldicarbonate (26.2 g)in DCM (50 ml) was added slowly and the reaction mixture was stirred at0° C. for 2 hours. The reaction mixture was allowed to warm to roomtemperature and stirred for 64 hours, then was washed with 1N citricacid (2×200 ml) and water (2×200 ml). The organic layer was dried(MgSO₄) and concentrated to givetert-butyl-(3S)-3-hydroxypiperidine-1-carboxylate as an oil (21.48 g,98%); NMR spectrum (DMSO-d₆ at 373K) 1.20-1.33 (m, 2H), 1.38 (s, 9H),1.54-1.67 (m, 1H), 1.72-1.85 (m, 1H), 2.53-2.68 (m, 1H), 2.69-2.83 (m,1H), 3.30-3.42 (m, 1H), 3.53-3.64 (m, 1H), 3.68-3.79 (m, 1H), 4.79 (d,1H).

Sodium hydride (60% dispersion in mineral oil, 623 mg) was addedportionwise to a stirred solution of thetert-butyl-(3S)-3-hydroxypiperidine-1-carboxylate (3.06 g) in DMA (50ml). Upon complete addition the reaction mixture was stirred for ½ hour.15-Crown-5 (50 mg) was added followed by2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as describedin example 21, preparation of starting materials) and the mixture heatedto 95° C. for 2 hours. Saturated ammonium chloride solution (10 ml) wasadded and the DMA was removed in vacuo. Water (150 ml) was added to theresidue and stirred vigorously. The resulting solid was filtered anddried. This was then stirred in hot diethyl ether (100 ml) for 10minutes and the cooled mixture filtered to givetert-butyl(3S)-3-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)piperidine-1-carboxylateas a yellow solid (2.4 g, 82%); NMR spectrum (DMSO-d6) 1.12 (s, 9H),1.57-1.84 (m, 2H), 2.00-2.18 (m, 2H), 3.08-3.24 (m, 1H), 3.43-3.57 (m,1H), 3.64-3.76 (m, 1H), 3.86-4.03 (m, 1H), 4.87-5.00 (m, 1H), 6.95-7.04(m, 1H), 7.18-7.41 (m, 3H), 7.68-7.85 (m, 2H), 8.49 (s, 1H), 9.80 (s,2H); Mass spectrum MH⁺ 471.

Tert-butyl(3S)-3-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)piperidine-1-carboxylate(1 g), picolyl chloride hydrochloride (384 mg) and potassium carbonate(737 mg) were stirred in DMF to which was added 18-crown-6 (0.1 g). Thereaction was stirred at room temperature for 2 days. The DMF was removedin-vacuo and the residue was partitioned between water and ethylacetate. The ethyl acetate was washed with water (3×100 ml) and brine(3×50 ml). This was dried (MgSO₄) and concentrated to givetert-butyl(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidine-1-carboxylateas a foam (1.1 g, 92%); NMR spectrum (CDCl₃) 1.21 (s, 9H), 1.54-1.71 (m,1H), 1.75-1.89 (m, 1H), 1.91-2.05 (m, 1H), 2.07-2.21 (m, 1H), 3.17-3.93(m, 4H), 4.56-4.69 (m, 1H), 5.23 (s, 2H), 6.83-6.99 (m, 2H), 7.11-7.20(m, 1H), 7.29-7.43 (m, 2H), 7.52-7.63 (m, 2H), 7.64-7.72 (m, 1H),7.83-7.90 (m, 1H), 8.47-8.57 (m, 2H), 9.71 (s, 1H); Mass spectrum MH⁺562.

tert-butyl(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidine-1-carboxylate(1.1 g) was stirred in TFA (15 ml) for 3 hours. The reaction mixture wasconcentrated and saturated potassium carbonate solution was added untilthe mixture was basic. This was diluted with water (20 ml) and stirredovernight. The precipitate was filtered and washed with water (100 ml).This was dried to giveN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-yloxy]quinazolin-4-amineas a solid (0.89 g, 99%); NMR spectrum (DMSO-d6) 1.37-1.51 (m, 1H),1.52-1.81 (m, 2H), 1.90-2.07 (m, 1H), 2.53-2.76 (m, 2H), 2.83-3.01 (m,2H), 3.07-3.18 (m, 1H), 4.88-4.98 (m, 1H), 5.27 (s, 2H), 7.14-7.25 (m,2H), 7.26-7.40 (m, 3H), 7.53-7.62 (m, 1H), 7.65-7.74 (m, 1H), 7.75-7.82(m, 1H), 7.83-7.93 (m, 1H), 8.50 (s, 1H), 8.58 (d, 1H), 10.74 (s, 1H);Mass spectrum MH⁺ 462.

EXAMPLE 302-{(3R)-3-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-yloxy]quinazolin-4-amine(32 mg, 29%); NMR spectrum (CDCl₃) 1.74-1.93 (m, 2H), 2.01-2.17 (m, 4H),3.19-3.30 (m, 1H), 3.47-3.67 (m, 1H), 3.70-3.85 (m, 1H), 3.90-4.10 (m,2H), 4.60-4.70 (m, 1H), 5.22 (s, 2H), 6.85-6.97 (m, 2H), 7.11-7.18 (m,1H), 7.22-7.35 (m, 1H), 7.38-7.47 (m, 1H), 7.52-7.62 (m, 2H), 7.63-7.72(m, 1H), 7.76 (s, 1H), 8.48-8.58 (m, 2H), 9.41-9.52 (m, 1H); Massspectrum MH⁺ 520.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-yloxy]quinazolin-4-amineused as starting material was prepared as described in example 29(preparation of starting materials) usingtert-butyl(3R)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidine-1-carboxylatein 100% yield; NMR spectrum (DMSO-d6) 1.37-1.51 (m, 1H), 1.52-1.81 (m,2H), 1.90-2.07 (m, 1H), 2.53-2.76 (m, 2H), 2.83-3.01 (m, 2H), 3.07-3.18(m, 1H), 4.88-4.98 (m, 1H), 5.27 (s, 2H), 7.14-7.25 (m, 2H), 7.26-7.40(m, 3H), 7.53-7.62 (m, 1H), 7.65-7.74 (m, 1H), 7.75-7.82 (m, 1H),7.83-7.93 (m, 1H), 8.50 (s, 1H), 8.58 (d, 1H), 10.74 (s, 1H); Massspectrum MH⁺ 462.

Thetert-butyl(3R)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidine-1-carboxylateused as starting material was prepared as described in example 29(preparation of starting materials) usingtert-butyl(3R)-3-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)piperidine-1-carboxylatein 92% yield; NMR spectrum (CDCl₃) 1.21 (s, 9H), 1.54-1.71 (m, 1H),1.75-1.89 (m, 1H), 1.91-2.05 (m, 1H), 2.07-2.21 (m, 1H), 3.17-3.93 (m,4H), 4.56-4.69 (m, 1H), 5.23 (s, 2H), 6.83-6.99 (m, 2H), 7.11-7.20 (m,1H), 7.29-7.43 (m, 2H), 7.52-7.63 (m, 2H), 7.64-7.72 (m, 1H), 7.83-7.90(m, 1H), 8.47-8.57 (m, 2H), 9.71 (s, 1H); Mass spectrum MH⁺ 562.

Thetert-butyl(3R)-3-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)piperidine-1-carboxylateused as starting material was prepared as described in example 29(preparation of starting materials) usingtert-butyl-(3R)-3-hydroxypiperidine-1-carboxylate and2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as describedin example 21, preparation of starting materials) in 72% yield; NMRspectrum (DMSO-d6 at 373K) 1.12 (s, 9H), 1.57-1.84 (m, 2H), 2.00-2.18(m, 2H), 3.08-3.24 (m, 1H), 3.43-3.57 (m, 1H), 3.64-3.76 (m, 1H),3.86-4.03 (m, 1H), 4.87-5.00 (m, 1H), 6.95-7.04 (m, 1H), 7.18-7.41 (m,3H), 7.68-7.85 (m, 2H), 8.49 (s, 1H), 9.80 (s, 2H); Mass spectrum MH⁺471.

The tert-butyl-(3R)-3-hydroxypiperidine-1-carboxylate used as startingmaterial was prepared as described in example 29 (preparation ofstarting materials) using (R)-3-hydoxypiperidine hydrochloride; NMRspectrum (DMSO-d6) 1.20-1.33 (m, 2H), 1.38 (s, 9H), 1.54-1.67 (m, 1H),1.72-1.85 (m, 1H), 2.53-2.68 (m, 1H), 2.69-2.83 (m, 1H), 3.30-3.42 (n,1H), 3.53-3.64 (m, 1H), 3.68-3.79 (m, 1H), 4.79 (d, 1H).

EXAMPLE 31N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S-piperidin-3-yloxy]quinazolin-4-amine(prepared as described in example 29, preparation of starting materials)in 17% yield; NMR spectrum (CDCl₃) 1.82-2.00 (m, 2H), 2.17 (s, 6H),2.22-2.45 (m, 1H), 2.72-2.85 (m, 1H), 2.94-3.14 (m, 2H), 3.26-3.47 (m,2H), 3.69-4.20 (m, 1H), 4.28-4.47 (m, 1H), 4.49-4.65 (m, 1H), 5.22 (s,2H), 6.94 (d, 1H), 7.13-7.26 (m, 3H), 7.34-7.44 (m, 2H), 7.52-7.63 (m,2H), 7.64-7.74 (m, 1H), 7.79-7.91 (m, 1H), 8.48-8.60 (m, 2H); Massspectrum MH⁺ 547.

EXAMPLE 32N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-yloxy]quinazolin-4-amine(prepared as described in example 30, preparation of starting materials)in 36% yield; NMR spectrum (CDCl₃) 1.81-2.00 (m, 2H), 2.15 (s, 6H),2.21-2.42 (m, 1H), 2.70-2.84 (m, 1H), 2.94-3.25 (m, 2H), 3.28-3.41 (m,2H), 3.68-4.18 (m, 1H), 4.28-4.46 (m, 1H), 4.48-4.64 (m, 1H), 5.22 (s,2H), 6.93 (d, 1H), 7.10-7.25 (m, 2H), 7.30-7.41 (m, 2H), 7.52-7.63 (m,2H), 7.64-7.72 (m, 1H), 7.79-7.90 (m, 1H), 8.48-8.57 (m, 2H), 9.58-9.77(m, 1H); Mass spectrum MH⁺ 547.

EXAMPLE 33(2R)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol

The procedure described in example 1 was repeated using D-lactic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(obtained as described example 1, preparation of starting materials) togive the title compound in 50% yield; NMR spectrum (DMSO-d6) 1.14 (d,3H), 1.98 (m, 3H), 3.44 (m, 1H), 3.70 (m, 1H), 4.26 (m, 2H), 4.42 (m,1H), 4.60 (bs, 1H), 4.78 (d, 1H), 5.30 (s, 2H), 7.24 (d, 1H), 7.27 (d,1H), 7.35 (m, 2H), 7.58 (m, 2H), 7.72 (t, 1H), 7.88 (dt, 1H), 8.01 (d,1H), 8.47 (s, 1H), 8.59 (d, 1H), 9.94 (bs, 1H); Mass spectrum MH⁺ 534.5.

EXAMPLE 342-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-methylpiperazin-2-yl]methoxy}quinazolin-4-aminehydrochloride to give the title compound in 28% yield; Mass spectrum MH⁺549.2.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-methylpiperazin-2-yl]methoxy}quinazolin-4-aninehydrochloride used as starting material was prepared as follows:

Trimethylsilyl diazomethane (2M in hexane, 14 ml) was added dropwise toa solution of (2R)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid(5 g) in methanol (100 ml) and DCM (115 ml), and the solution stirred atroom temperature for 16 hours. The solvent was concentrated in vacuo andthe residue purified by chromatography, eluting with ethyl acetate then5% methanol/7N ammonia in ethyl acetate, to give 1-tert-butyl2-methyl(2R)-piperazine-1,2-dicarboxylate as an oil (2.55 g, 48%); NMRspectrum (DMSO-d6) 1.40 (s, 9H), 2.10 (bs, 1H), 2.52 (m, 1H), 2.72 (dd,1H), 2.82 (d, 1H), 2.97 (m, 1H), 3.29 (d, 1H), 3.61 (d, 1H), 3.67 (s,3H), 4.43 (m, 1H); Mass spectrum MH⁺ 245.

Lithium aluminium hydride (1M in THF, 26 ml) was added to a solution of1-tert-butyl 2-methyl(2R)-piperazine-1,2-dicarboxylate (2.55 g) in THF(70 ml) at −40° C., then the reaction was warmed to room temperature.The solution was stirred for 1 hour, then cooled to 0° C. and quenchedby sequential addition of water (1 ml), sodium hydroxide (2N, 1 ml) andthen water (2 ml). The resulting slurry was filtered and concentrated invacuo to give tert-butyl(2R)-2-(hydroxymethyl)piperazine-1-carboxylate(2.37 g, >100%); NMR spectrum (DMSO-d6, 373K) 1.40 (s, 9H), 2.58 (m,1H), 2.82 (m, 3H), 2.92 (bs, 1H), 2.98 (d, 1H), 3.43 (m, 1H), 3.65 (m,2H), 3.80 (m, 1H); Mass spectrum MH⁺ 217.

Lithium aluminium hydride (1M in THF, 17.6 ml) was added to a solutionof tert-butyl(2R)-2-(hydroxymethyl)piperazine-1-carboxylate (1.27 g) inTHF (40 ml) at 0° C., then the reaction was warmed to room temperature.The solution was stirred for 3 hours, then heated at reflux for 1 hour,cooled to 0° C. and quenched by sequential addition of water (0.2 ml),sodium hydroxide (2N, 0.2 ml) and then water (0.4 ml). The resultingslurry was filtered and concentrated in vacuo to give[(2R)-1-methylpiperazin-2-yl]methanol (0.44 g); Mass spectrum MH⁺ 131.

Sodium hydride (60% dispersion in mineral oil, 0.27 g) was added to[(2R)-1-methylpiperazin-2-yl]methanol (0.44 g) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(0.43 g, obtained as described in example 1, preparation of startingmaterials) in DMA (20 ml) and the reaction heated at 90° C. for 16hours. The reaction was cooled, quenched with water, and concentrated invacuo. The residue was purified by reverse phase chromatography, using10-40% acetonitrile in water with 0.2% TFA modifier as eluent, to giveafter acidification with HCl in ether,N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-methylpiperazin-2-yl]methoxy}quinazolin-4-aminehydrochloride as a white solid (82 mg, 15%); NMR spectrum (DMSO-d6) 2.40(s, 3H), 2.69 (dt, 1H), 2.82 (dt, 1H), 2.83 (m, 1H), 2.98 (m, 1H), 3.15(t, 1H), 3.27 (m, 1H), 3.37 (m, 1H), 4.52 (m, 2H), 5.31 (s, 2H), 7.32(m, 3H), 7.47 (d, 1H), 7.58 (d, 1H), 7.67 (dd, 1H), 7.85 (dt, 1H), 7.87(d, 1H), 7.92 (t, 1H), 8.57 (d, 1H), 8.72 (s, 1H); Mass spectrum MH⁺491.4.

EXAMPLE 352-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-pyridin-2-ylmethoxy)phenyl]-5-{[(2S)-1-methylpiperazin-2-yl]methoxy}quinazolin-4-amineto give the title compound in 34% yield; Mass spectrum MH⁺ 549.3.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2SR)-1-methylpiperazin-2-yl]methoxy}quinazolin-4-amineused as starting material was prepared as follows:

Lithium aluminium hydride (1M in THF, 19.5 ml) was added to a solutionof (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.5 g) inTHF (20 ml) at 0° C., then the reaction was warmed to room temperatureand heated at 60° C. for 16 hours. The reaction was cooled to 0° C. andquenched by sequential addition of water (0.75 ml), sodium hydroxide(2N, 0.75 ml) and then water (1.5 ml). The resulting slurry was filteredand concentrated in vacuo and the residue purified by chromatographyusing DCM to 20% 7N ammonia in methanol in DCM to[(2S)-1-methylpiperazin-2-yl]methanol as a white solid (454 mg, 53%);NMR spectrum (DMSO-d6) 1.83 (m, 1H), 1.98 (dt, 1H), 2.14 (s, 3H), 2.31(dd, 1H), 2.56 (m, 2H), 2.68 (m, 1H), 2.84 (dd, 1H), 3.23 (dd, 1H), 3.52(dd, 1H).

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2SR)-1-methylpiperazin-2-yl]methoxy}quinazolin-4-aminewas prepared as described in example 34 (preparation of startingmaterials) using [(2S)-1-methylpiperazin-2-yl]methanol andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(obtained as described in example 1, preparation of starting materials)in 17% yield; NMR spectrum (DMSO-d6) 2.23 (dt, 1H), 2.30 (s, 3H), 2.32(m, 1H), 2.60 (dt, 1H), 2.76 (m, 3H), 2.87 (dd, 1H), 4.24 (d, 1H), 4.44(dd, 1H), 5.25 (s, 2H), 7.09 (dd, 1H), 7.26 (d, 1H), 7.34 (m, 2H), 7.57(d, 1H), 7.71 (t, 1H), 7.88 (m, 2H), 7.98 (d, 1H), 8.51 (s, 1H), 8.58(m, 1H), 10.42 (bs, 1H); Mass spectrum MH⁺ 491.

EXAMPLE 362-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-aminein 31% yield; Mass spectrum M⁺ 548.9.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-amineused as starting material was prepared as follows:

[(2R)-4-methylpiperazin-2-yl]methanol was prepared as described inexample 35 (preparation of starting materials) using(2R)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid as startingmaterial in 61% yield; NMR spectrum (DMSO-d6, 373K) 1.63 (t, 1H), 1.88(dt, 1H), 2.13 (s, 3H), 2.52 (m, 1H), 2.60 (m, 1H), 2.67 (m, 2H), 2.81(dt, 1H), 3.30 (d, 2H).

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-aminewas prepared as described in example 34 (preparation of startingmaterials) using [(2R)-4-methylpiperazin-2-yl]methanol andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(obtained as described in example 1, preparation of starting materials)in 51% yield; NMR spectrum (DMSO-d6) 1.88 (m, 2H), 2.14 (s, 3H), 2.62(d, 1H), 2.73 (d, 1H), 2.81 (m, 1H), 2.98 (d, 1H), 3.20 (m, 1H), 4.21(m, 1H), 4.31 (m, 1H), 5.29 (s, 2H), 7.10 (d, 1H), 7.27 (d, 1H), 7.35(d, 1H), 7.37 (m, 1H), 7.58 (d, 1H), 7.72 (t, 1H), 7.90 (dt, 1H), 7.92(dd, 1H), 8.09 (d, 1H), 8.52 (s, 1H), 8.60 (d, 1H), 10.58 (s, 1H); Massspectrum MH⁺ 491.

EXAMPLE 372-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-f{[(2S)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-aminein 44% yield; Mass spectrum M⁺ 548.9.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2S)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-amineused as starting material was prepared as follows:

[(2S)-4-methylpiperazin-2-yl]methanol was prepared as described inexample 36, preparation of starting materials, for the R-antipode using(2S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid as startingmaterial in 52% yield.

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2S)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-aminewas prepared as described in example 36, preparation of startingmaterials, for the R-antipode using[(2S)-4-methylpiperazin-2-yl]methanol as starting material in 43% yield.

EXAMPLE 382-((2R)-2-{(1S)-1-[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using2-(chloromethyl)pyridine and2-chloro-4-[(5-{(1S)-1-[(2R)-1-glycoloylpyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenolto give the title compound in 17% yield; NMR spectrum (DMSO-d6) 1.35 (d,3H), 1.95 (m, 4H), 3.44 (t, 2H), 4.01 (dq, 2H), 4.55 (m, 2H), 5.15 (on,1H), 5.30 (s, 2H), 7.24 (d, 1H), 7.32 (d, 1H), 7.35 (m, 1H), 7.43 (d,1H), 7.57 (d, 1H), 7.62 (dd, 1H), 7.73 (dd, 1H), 7.87 (dt, 1H), 8.17 (d,1H), 8.48 (s, 1H), 8.58 (m, 1H), 10.10 (s, 1H); Mass spectrum MH⁺ 534.

The2-chloro-4-[(5-{(1S)-1-[(2R)-1-glycoloylpyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as follows:

1-(tert-butoxycarbonyl)-D-proline (10.24 g) in DCM (240 ml) andtriethylamine (6.94 ml) were vigorously stirred at −5° C.Isobutylchloroformate (6.6 g) was added dropwise maintaining thetemperature below −7° C. The solution was stirred for 30 minutes.N,O-Dimethylhydroxylamine hydrochloride (4.8 g) was added, thentriethylamine (6.9 ml) dropwise. The solution was stirred for 1 hour andallowed to warm to 0° C. The solution was stirred for a further 3 hourswhereupon the temperature had reached ambient. The solution was washedwith saturated sodium hydrogen carbonate solution, water, brine and wasdried (MgSO₄) and evaporated to give1-(tert-butoxycarbonyl)-N-methoxy-N-methyl-D-prolinamide (9.4 g, 76%);NMR spectrum (CDCl₃) 1.40 and 1.43 (each s, together 9H), 2.00 (m, 4H),3.20 (s, 3H), 3.50 (m, 2H), 3.70 and 3.79 (each s, together 3H), 4.64(ddd, 1H).

1-(tert-Butoxycarbonyl)-N-methoxy-N-methyl-D-prolinamide (6.67 g) in THF(70 ml) at −9° C. under nitrogen was treated with methylmagnesiumbromide (3.0 M in diethyl ether) (13 ml) dropwise keeping thetemperature below −8° C. The ice bath was left in place and stirringcontinued overnight. Ethyl acetate (60 ml) was added followed by 2N HCland the solution extracted with ethyl acetate (2×). The combined organicextracts were washed with saturated sodium hydrogen carbonate solution,water, brine and dried (MgSO₄) and evaporated to givetert-butyl(2R)-2-acetylpyrrolidine-1-carboxylate (4.82 g, 87%); NMRspectrum (CDCl₃) 1.42 (s, 9H), 1.85 (m, 4H), 2.12 (s, 3H), 3.51 (m, 2H),4.26 (m, 1H).

tert-Butyl(2R)-2-acetylpyrrolidine-1-carboxylate (4.14 g) in THF (90 ml)at 0° C. was treated with lithium aluminium hydride (1.0 M in THF) (5.79ml) and stirred for 50 minutes. Water (0.22 ml) was added followed by15% NaOH (0.22 ml) then water (0.66 ml) and the mixture filtered andevaporated to givetert-butyl(2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (3.72 g,89%); NMR spectrum (DMSO-d6) 0.95 and 1.01 (each d, together 6H), 1.42(s, 18H), 1.80 (m, 8H), 3.19 (m, 2H), 3.39 (m, 2H), 3.58 (m, 2H), 3.75(m, 2H), 3.88 (m, 2H), 4.11 (d, 1H), 4.20 (d, 1H).

tert-Butyl(2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (2.05 g) indiethyl ether (15 ml) was treated with HCl (1.0 M in diethyl ether) (35ml) and stirred overnight. The solution was then taken to pH10 withammonium hydroxide, extracted with DCM (8×) and the extracts purified bychromatography using DCM—10% methanol/NH₄OH as eluant to give1-[(2R)-pyrrolidin-2-yl]ethanol as a 1:1 mixture of diastereoisomers(0.86 g, 78%); NMR spectrum (DMSO-d6) 1.07 (d, J=2.0 Hz, 3H), 1.09 (d,J=2.3 Hz, 3H), 1.36 (m, 1H), 1.69 (m, 7H), 2.76 (m, 1H), 2.88 (m, 8H),3.06 (m, 1H), 3.29 (m, 1H), 3.75 (m, 1H).

2-Chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as describedin example 21, preparation of starting materials, 2.0 g) in DMA (30 g)was treated with 1-[(2R)-pyrrolidin-2-yl]ethanol (1.98 g) and sodiumhydride (60% in oil) (0.69 g) and heated in a microwave at 140° C. for15 minutes over several batches. The mixture was evaporated and purifiedby chromatography using DCM—10% methanol/NH₄OH as eluant to give2-chloro-4-[(5-{(1S)-1-[(2R)-pyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenol(0.171 g, 6%); NMR spectrum (DMSO-d6) 1.38 (d, 3H), 1.50 (m, 1H), 1.60(m, 2H), 1.82 (m, 1H), 2.78 (m, 2H), 3.28 (m, 2H), 4.70 (m, 1H), 6.95(d, 1H), 7.13 (d, 1H), 7.29 (m, 2H), 7.60 (dd, 1H), 7.67 (t, 1H), 7.95(d, 1H), 8.44 (s, 1H), 10.66 (s, 1H); and2-chloro-4-[(5-{(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenol(0.094 g, 4%/0); NMR spectrum (DMSO-d6) 1.35 (d, 3H), 1.53 (m, 1H), 1.68(m, 2H), 1.90 (m, 1H), 2.80 (m, 1H), 2.85 (m, 1H), 3.30 (m, 2H), 3.50(m, 1H), 4.75 (m, 1H), 7.00 (d, 1H), 7.20 (d, 1H), 7.28 (d, 1H), 7.50(d, 1H), 7.69 (t, 1H), 7.98 (s, 1H), 8.47 (s, 1H), 10.35 (s, 1H).

2-chloro-4-[(5-{(1S)-1-[(2R)-1-glycoloylpyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenolwas prepared as described in example 21 (preparation of startingmaterials) using2-chloro-4-[(5-{(1S)-1-[(2R)-pyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenoland glycolic acid in 63% yield.

EXAMPLE 392-((2R)-2-{(1R)-1-[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using2-(chloromethyl)pyridine and2-chloro-4-[(5-{(1R)-1-[(2R)-1-glycoloylpyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenolto give the title compound in 31% yield; NMR spectrum (DMSO-d6) 1.40 (d,3H), 1.80 (m, 2H), 2.00 (m, 1H), 2.10 (m, 1H), 3.12 (m, 1H), 3.42 (m,1H), 3.85 (dd, 1H), 4.03 (dd, 1H), 4.33 (m, 1H), 4.51 (n, 1H), 5.25 (dd,1H), 5.30 (s, 2H), 7.08 (d, 1H), 7.26 (d, 1H), 7.32 (d, 1H), 7.35 (m,1H), 7.51 (dd, 1H), 7.58 (d, 1H), 7.69 (t, 1H), 7.87 (dt, 1H), 8.07 (dd,1H), 8.48 (s, 1H), 8.58 (d, 1H), 10.01 (s, 1H); Mass spectrum MH⁺ 534.

The2-chloro-4-[(5-{(1R)-1-[(2R)-1-glycoloylpyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as described in example 38(preparation of starting materials) using2-chloro-4-[(5-{(1R)-1-[(2R)-pyrrolidin-2-yl]ethoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 38, preparation of starting materials)and glycolic acid in 61% yield.

EXAMPLE 402-[(2S-2-({[4-({3-Chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure described in example 25 was repeated using(6-methylpyridin-2-yl)methanol and2-chloro-4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolto give the title compound in 65% yield; NMR spectrum (DMSO-d6)1.94-2.12 (m, 4H), 3.43-3.50 (m, 2H), 3.61 (s, 1H), 4.03-4.15 (m, 1H),4.23-4.29 (m, 1H), 4.48-4.54 (m, 1H), 4.56-4.62 (m, 1H), 4.63-4.69 (m,1H), 5.31 (s, 2H), 7.26-7.34 (m, 3H), 7.38-7.46 (m, 2H), 7.62-7.67 (m,1H), 7.76-7.85 (m, 2H), 8.09 (d, 1H), 8.54 (s, 1H), 10.05 (s, 1H); Massspectrum MH⁺ 534.

The2-chloro-4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as follows:

2-Chloro-4-({5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolwas prepared as described in example 21 (preparation of startingmaterials) using 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol and(2S)-pyrrolidin-2-ylmethanol in 88% yield; NMR spectrum (DMSO-d6)1.53-1.68 (m, 1H), 1.71-1.89 (m, 2H), 1.93-2.09 (m, 1H), 3.02 (t, 2H),3.18-3.42 (m, 2H), 3.74-3.8.8 (m, 1H), 4.29 (t, 1H), 4.36-4.45 (m, 1H),6.98 (d, 1H), 7.15 (d, 1H), 7.33 (d, 1H), 7.50-7.58 (m, 1H), 7.66-7.75(m, 1H), 7.93-7.97 (m, 1H), 8.48 (s, 1H), 10.05 (s, 1H); Mass spectrumMH⁺ 371.

2-Chloro-4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolwas prepared as described in example 21 (preparation of startingmaterials) using2-chloro-4-({5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenoland glycolic acid in 98% yield; NMR spectrum (DMSO-d6) 1.84-2.09 (m,5H), 3.94-4.10 (m, 2H), 4.22-4.31 (m, 1H), 4.46 (t, 1H), 4.56-4.66 (m,1H), 7.03-7.10 (m, 2H), 7.34-7.51 (m, 4H), 7.70 (s, 1H), 7.90-7.99 (m,1H), 8.73 (s, 1H), 10.45 (s, 1H), 10.92 (s, 1H); Mass spectrum MH⁺ 429.

EXAMPLE 412-[(2S)-2-({[4-({3-Chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using1-(chloromethyl)-2-fluorobenzene and2-chloro-4-[(5-{[(25)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 40, preparation of starting materials)to give the title compound in 61% yield; NMR spectrum (DMSO-d6)1.88-2.07 (m, 4H), 3.38-3.45 (m, 2H), 3.55 (s, 1H), 3.98-4.11 (m, 1H),4.18-4.25 (m, 1H), 4.43-4.49 (m, 1H), 4.51-4.56 (m, 1H), 4.57-4.64 (m,1H), 5.27 (s, 2H), 7.24-7.38 (m, 5H), 7.42-7.48 (m, 1H), 7.59-7.65 (m,2H), 7.70-7.76 (m, 1H), 8.02 (d, 1H), 8.48 (s, 1H), 9.99 (s, 1H); Massspectrum MH⁺ 537.

EXAMPLE 422-[(2S)-2-({[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using1-(chloromethyl)-3-fluorobenzene and2-chloro-4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-yl)amino]phenol(obtained as described in example 40, preparation of starting materials)to give the title compound in 61% yield; NMR spectrum (DMSO-d6)1.94-2.12 (m, 4H), 3.42-3.50 (m, 2H), 3.61 (s, 1H), 4.03-4.15 (m, 1H),4.23-4.29 (m, 1H), 4.48-4.54 (m, 1H), 4.56-4.61 (m, 1H), 4.63-4.69 (m,1H), 5.32 (s, 2H), 7.21-7.27 (m, 1H), 7.28-7.34 (m, 2H), 7.35-7.44 (m,3H), 7.50-7.56 (m, 1H), 7.63-7.68 (m, 1H), 7.76-7.82 (m, 1H), 8.08 (d,1H), 8.53 (s, 1H), 10.04 (s, 1H); Mass spectrum MH⁺ 537.

EXAMPLE 432-((2S)-2-{[(4-{[3-Chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using4-(chloromethyl)-1,3-thiazole and2-chloro-4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 40, preparation of starting materials)to give the title compound in 49% yield; NMR spectrum (DMSO-d6)1.89-2.07 (m, 4H), 3.38-3.44 (m, 2H), 3.55 (s, 1H), 4.04 (t, 1H),4.18-4.24 (m, 1H), 4.43-4.49 (m, 1H), 4.53 (t, 1H), 4.57-4.63 (m, 1H),5.35 (s, 2H), 7.26 (d, 1H), 7.35 (d, 2H), 7.58-7.63 (m, 1H), 7.70-7.76(m, 1H), 7.82 (d, 1H), 8.02 (d, 1H), 8.48 (s, 1H), 9.16 (d, 1H), 9.98(s, 1H); Mass spectrum MH⁺ 526.

EXAMPLE 442-((2S)-2-{[(4-{[3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 25 was repeated usingpyrazin-2-ylmethanol and2-chloro-4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 40, preparation of starting materials)to give the title compound in 57% yield; NMR spectrum (DMSO-d6)1.89-2.07 (m, 4H), 3.38-3.44 (m, 2H), 3.55 (s, 0H), 4.04 (t, 1H),4.19-4.24 (m, 1H), 4.43-4.49 (m, 1H), 4.51-4.55 (m, 1H), 4.57-4.65 (m,1H), 5.39 (s, 2H), 7.26 (d, 1H), 7.31-7.37 (m, 2H), 7.60-7.64 (m, 1H),7.70-7.76 (m, 1H), 8.05 (d, 1H), 8.48 (s, 1H), 8.65-8.71 (m, 2H),8.86-8.89 (m, 1H), 10.00 (s, 1H); Mass spectrum MH⁺ 521.

EXAMPLE 45N-{3-Chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 25 was repeated using(6-methylpyridin-2-yl)methanol and2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolto give the title compound in 24% yield; NMR spectrum (DMSO-d6)1.90-2.11 (m, 4H), 2.20-2.26 (m, 6H), 3.04 (d, 1H), 3.17 (d, 1H),3.56-3.65 (m, 2H), 4.23-4.30 (m, 1H), 4.44-4.49 (m, 1H), 4.60-4.67 (m,1H), 5.30 (s, 2H), 7.28 (d, 3H), 7.37-7.44 (m, 2H), 7.63-7.67 (m, 1H),7.75-7.84 (m, 2H), 8.08 (d, 1H), 8.51 (s, 1H), 10.03 (s, 1H), 2.56 (s,3H); Mass spectrum MH⁺ 561.

The2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as described in example 21(preparation of starting materials) using N,N-dimethylglycine and2-chloro-({5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 40, preparation of starting materials)in 93% yield; NMR spectrum (DMSO-d6) 1.85-2.08 (m, 4H), 2.33 (s, 6H),3.23-3.40 (m, 2H), 3.46-3.54 (m, 2H), 4.15-4.24 (m, 1H), 4.36-4.45 (m,1H), 4.51-4.61 (m, 1H), 6.98 (d, 1H), 7.20 (d, 1H), 7.27-7.33 (m, 1H),7.37-7.43 (m, 1H), 7.65-7.73 (m, 1H), 7.86 (d, 1H), 8.42 (s, 1H), 9.85(s, 1H), 10.06 (s, 1H); Mass spectrum MH⁺ 456.

EXAMPLE 46N-{3-Chloro-4-[(2-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 21 was repeated using1-(chloromethyl)-2-fluorobenzene and2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 45, preparation of starting materials)to give the title compound in 26% yield; NMR spectrum (DMSO-d6)1.85-2.07 (m, 4H), 2.17-2.22 (m, 6H), 3.01 (d, 1H), 3.14 (d, 1H),3.52-3.59 (m, 2H), 4.19-4.24 (m, 1H), 4.39-4.45 (m, 1H), 4.56-4.62 (m,1H), 5.27 (s, 2H), 7.21-7.37 (m, 5H), 7.42-7.48 (m, 1H), 7.58-7.65 (m,2H), 7.70-7.75 (m, 1H), 8.00 (d, 1H), 8.47 (s, 1H), 9.98 (s, 1H); Massspectrum MH⁺ 564.

EXAMPLE 47N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 21 was repeated using1-(chloromethyl)-3-fluorobenzene and2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 45, preparation of starting materials)to give the title compound in 14% yield; NMR spectrum (DMSO-d6)1.87-2.08 (m, 4H), 2.25-2.33 (m, 6H), 3.27 (s, 2H), 3.50-3.56 (m, 2H),4.19-4.25 (m, 1H), 4.40-4.46 (m, 1H), 4.56-4.64 (m, 1H), 5.27 (s, 2H),7.15-7.27 (m, 3H), 7.29-7.36 (m, 3H), 7.44-7.51 (m, 1H), 7.59-7.63 (m,1H), 7.70-7.75 (m, 1H), 8.01 (d, 1H), 8.47 (s, 1H), 9.98 (s, 1H); Massspectrum MH⁺ 564.

EXAMPLE 48N-[3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 25 was repeated usingpyrazin-2-ylmethanol and2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 45, preparation of starting materials)to give the title compound in 19% yield; NMR spectrum (DMSO-d6)1.86-2.07 (m, 4H), 2.20 (s, 6H), 3.02 (d, 1H), 3.15 (d, 1H), 3.52-3.59(m, 2H), 4.18-4.25 (m, 1H), 4.39-4.45 (m, 1H), 4.56-4.63 (m, 1H), 5.40(s, 2H), 7.23 (d, 1H), 7.30-7.36 (m, 2H), 7.60-7.65 (m, 1H), 7.70-7.75(m, 1H), 8.03 (d, 1H), 8.47 (s, 1H), 8.65-8.72 (m, 2H), 8.87 (s, 1H),10.00 (s, 1H); Mass spectrum MH⁺ 548.

EXAMPLE 49N-[3-Chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 21 was repeated using4-(chloromethyl)-1,3-thiazole and2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 45, preparation of starting materials)in to give the title compound 1% yield; Mass spectrum MH⁺ 553.

EXAMPLE 50 2-[(2R)-2-({[4-({3-Chloro4[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure described in example 25 was repeated using(6-methylpyridin-2-yl)methanol and2-chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-yl)amino]phenolto give the title compound in 35% yield; NMR spectrum (DMSO-d6)1.34-1.52 (m, 1H), 1.57-1.76 (m, 4H), 1.82-1.91 (m, 1H), 3.27-3.32 (m,4H), 3.50-3.65 (m, 1H), 3.92-4.14 (m, 2H), 4.18-4.45 (m, 2H), 4.71 (t,1H), 5.11-5.22 (m, 1H), 5.25 (s, 2H), 7.22 (d, 1H), 7.24 (d, 1H), 7.29(d, 1H), 7.33-7.40 (m, 2H), 7.54 (d, 1H), 7.71-7.79 (m, 2H), 7.95 (s,1H), 8.45 (s, 1H), 9.66 (s, 1H); Mass spectrum MH⁺ 548.

The2-chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as follows:

2-Chloro-4-(f{5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolwas prepared as described in example 21 (preparation of startingmaterials) using (2R)-piperidin-2-ylmethanol and2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol in 71% yield; Massspectrum MH⁺ 384.

2-Chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolwas prepared as described in example 1 (preparation of startingmaterials) using glycolic acid and2-chloro-4-({5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolin 73% yield; Mass spectrum MH⁺ 443.

EXAMPLE 512-[(2R)-2-({[4-({3-Chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using1-(chloromethyl)-2-fluorobenzene and2-chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 50, preparation of starting materials)to give the title compound in 40% yield; NMR spectrum (DMSO-d6)1.34-1.51 (m, 1H), 1.57-1.78 (m, 4H), 1.82-1.93 (m, 1H), 3.49-3.65 (m,3H), 3.91-4.16 (m, 2H), 4.19-4.45 (m, 2H), 4.12 (t, 1H), 5.27 (s, 2H),7.23-7.39 (m, 5H), 7.41-7.50 (m, 1H), 7.52-7.66 (m, 2H), 7.69-7.79 (m,1H), 7.93 (s, 1H), 8.41-8.50 (m, 1H), 9.68 (s, 1H); Mass spectrum MH⁺551.

EXAMPLE 522-[(2R)-2-({[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using1-(chloromethyl)-3-fluorobenzene and2-chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 50, preparation of starting materials)in to give the title compound 44% yield; NMR spectrum (DMSO-d6)1.35-1.51 (m, 1H), 1.57-1.77 (m, 4H), 1.82-1.91 (m, 1H), 3.51-3.59 (m,3H), 3.91-4.15 (m, 2H), 4.17-4.42 (m, 2H), 4.72 (t, 1H), 5.27 (s, 2H),7.14-7.40 (m, 6H), 7.44-7.59 (m, 2H), 7.70-7.78 (m, 1H), 7.90-7.97 (m,1H), 8.45 (s, 1H), 9.66 (s, 1H); Mass spectrum MH⁺ 551.

EXAMPLE 532-((2R-2-{[(4-{[3-Chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using4-(chloromethyl)-1,3-thiazole and2-chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 50, preparation of starting materials)to give the title compound in 34% yield; NMR spectrum (DMSO-d6)1.33-1.52 (m, 1H), 1.56-1.78 (m, 4H), 1.81-1.93 (m, 1H), 3.55 (s, 3H),3.90-4.16 (m, 2H), 4.17-4.45 (m, 2H), 4.71 (t, 1H), 5.34 (s, 2H),7.23-7.42 (m, 3H), 7.55 (d, 1H), 7.69-7.78 (m, 1H), 7.82 (s, 1H), 7.93(s, 1H), 8.45 (s, 1H), 9.16 (s, 1H), 9.66 (s, 1H); Mass spectrum M-H⁺539.

EXAMPLE 542-((2R)-2-{[(4-{[3-Chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 25 was repeated usingpyrazin-2-ylmethanol and2-chloro-4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol(obtained as described in example 50, preparation of starting materials)to give the title compound in 43% yield; NMR spectrum (DMSO-d6)1.35-1.51 (m, 1H), 1.58-1.76 (m, 4H), 1.82-1.91 (m, 1H), 3.28 (s, 2H),3.55 (s, 1H), 3.90-4.15 (m, 2H), 4.19-4.45 (m, 2H), 4.72 (t, 1H), 5.39(s, 2H), 7.25-7.38 (m, 3H), 7.54-7.60 (m, 1H), 7.71-7.78 (m, 1H), 7.96(s, 1H), 8.46 (s, 1H), 8.65-8.72 (m, 1H), 8.88 (s, 1H), 9.67 (s, 1H);Mass spectrum MH⁺ 535.

EXAMPLE 552-[(2R)-2-({[4-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

Acetoxyacetyl chloride (50 μl, 0.5 mmol) was added dropwise to anice-cooled solution ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) and triethylamine (80 μl, 0.54 mmol) in DCM (5 ml).The mixture was stirred at room temperature for 2 hours. Afterevaporation of the mixture to dryness, pyrrolidine (0.19 ml, 2.26 mmol)was added and the mixture was stirred at 80° C. for 1 hour. Afterevaporation of the solvents, the residue was purified on an HPLC column(C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MSsystem eluting with a mixture of water and acetonitrile containing 2 g/lof ammonium formate (gradient), then triturated in ether to give thetitle compound (55 mg, 24%) as a pale solid; NMR spectrum (CDCl₃)2.2-2.1 (m, 4H), 2.29 (s, 3H), 2.53 (s, 3H), 3.30 (m, 1H), 3.43-3.35 (m,2H), 4.12 (m, 3H), 4.55 (m, 1H), 4.76 (m, 1H), 6.91 (d, 1H), 6.99 (d,1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.44 (d, 1H), 7.50 (d, 1H), 7.63 (m,2H), 8.28 (s, 1H), 8.62 (s, 1H), 9.78 (s br, 1H); Mass spectrum: MH⁺500.

TheN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amineused as starting material was made as follows:

Sodium hydride (25.6 g, 60% dispersion in oil, 0.64 mol) was addedportion wise to a solution of 5-hydroxy-2-methylpyridine (70 g, 0.64mol) in DMA (700 ml) while keeping the temperature below 40° C. At theend of the addition, the mixture was stirred at room temperature for 1hour and 2-fluoro-5-nitrotoluene (91.3 g, 0.59 mol) in DMA (100 ml) wasadded slowly. The mixture was stirred at 80° C. for 3 hours and thencooled. The solvents were evaporated under vacuum and the residue waspartitioned between ethyl acetate and water. The organic layer waswashed with water and brine, dried over MgSO₄. After evaporation of thesolvents, the residue was purified by chromatography on silica gel(eluant: 30% ethyl acetate in petroleum ether) to give2-methyl-5-(2-methyl nitrophenoxy)pyridine (141 g, 98%) as an oil; NMRspectrum (CDCl₃); 2.43 (s, 3H), 2.59 (s, 3H), 6.74 (d, 1H), 7.21 (d,1H), 7.27 (d, 1H), 8.00 (d, 1H), 8.17 (s, 1H), 8.32 (s, 1H).

A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) andethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar)for 5 hours. After reaction completion, the mixture was purged withnitrogen and the catalyst was filtered off. The filtrate was evaporatedto dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (120.6g, 98%) as a white solid; Mass spectrum MH⁺ 215.

3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4Nhydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to asuspension of 4-chloro-5-fluoroquinazoline (5 g, 27.5 mmol; PCT Int.Appl. WO2001094341, AstraZeneca) in acetonitrile (100 ml). The mixturewas stirred at 80° C. for 2 hours. After cooling, the precipitate waswashed with acetonitrile. This precipitate was partitioned between DCMand 5% aqueous sodium bicarbonate and the pH was adjusted to 8. Theorganic layer was washed with brine and dried over MgSO₄. Evaporation ofthe solvents gave5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine(9.3 g, 94%) as a dark gum which crystallised on standing; NMR spectrum(CDCl₃); 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H),7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H),8.37 (d, 1H), 8.71 (s, 1H).

Sodium hydride (228 mg, 60% dispersion in oil, 5.7 mmol) was addedportion wise to a solution of (R)-2-pyrrolidinemethanol (562 mg, 5.56mmol) in THF (20 ml). 15-Crown-5 (120 mg, 0.56 mmol) was added and themixture was stirred at room temperature for 15 minutes.5-Fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine(1 g, 2.78 mmol) was added. The mixture was heated at reflux for 15hours. After cooling, the solvents were evaporated under vacuum andbrine was added. The mixture was extracted with DCM. The organic layerwas dried over MgSO₄. After evaporation of the solvents, the residue waspurified by chromatography on silica gel (eluant: 7 to 10% methanol inDCM), then triturated in ether to giveN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(930 mg, 76%) as a beige solid, NMR spectrum (CDCl₃) 1.66 (m, 1H),2.0-1.8 (m, 2H), 2.03 (m, 1H), 2.28 (s, 3H, 2.53 (s, 3H), 3.02 (m, 2H),3.74 (m, 1H), 4.08 (m, 1H), 4.20 (m, 1H), 6.90 (m, 2H), 7.08 (d, 1H),7.13 (d, 1H), 7.44 (d, 1H), 7.62 (m, 2H), 7.75 (s, 1H), 8.27 (s, 1H),8.63 (s, 1H); Mass spectrum: MH⁺ 442.

EXAMPLE 565-({(2R)-1-[(Dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine

Dimethylaminoacetyl chloride (126 mg, 0.8 mmol) was added dropwise to anice-cooled solution ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) and triethylamine (260 μl, 1.8 mmol) in DCM (5 ml).The mixture was stirred at room temperature for 2 hours. Afterevaporation of the mixture to dryness, the residue was purified on anHPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of apreparative HPLC-MS system eluting with a mixture of water andacetonitrile containing 2 g/l of ammonium formate (gradient), thentriturated in ether to give the title compound (170 mg, 71%) as a palesolid; NMR spectrum (CDCl₃) 2.16-2.03 (m, 4H), 2.29 (s, 3H), 2.33 (s,6H), 2.53 (s, 3H), 3.06 (d, 1H), 3.14 (d, 1H), 3.60 (m, 2H), 4.06 (t,1H), 4.62 (m, 1H), 4.68 (m, 1H), 6.91 (d, 1H), 7.14-7.07 (m, 3H), 7.47(m, 2H), 7.64 (m, 2H), 8.27 (s, 1H), 8.62 (s, 1H), 9.80 (s br, 1H); Massspectrum: MH⁺ 527.

EXAMPLE 572-[(25)-2-({[4-({3-Methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure described in example 55 was repeated withN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) to give the title compound (85 mg, 35%) as a palesolid; NMR spectrum (CDCl₃) 2.2-2.1 (m, 4H), 2.30 (s, 3H), 2.54 (s, 3H),3.28 (m, 1H), 3.43-3.35 (m, 2H), 4.12 (m, 3H), 4.55 (m, 1H), 4.76 (m,1H), 6.91 (d, 1H), 6.99 (d, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.44 (d,1H), 7.50 (d, 1H), 7.63 (m, 2H), 8.28 (s, 1H), 8.62 (s, 1H), 9.81 (s br,1H); Mass spectrum: MH⁺ 500.

TheN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amineused as starting material was made from (S)-2-pyrrolidinemethanol (562mg, 5.56 mmol) and5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine(1 g, 2.78 mmol) according to the procedure described in Example 55starting material (889 mg, 72%); Mass spectrum: MH⁺ 442.

EXAMPLE 585-({(2S)-1-[(Dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine

The procedure described in example 56 was repeated withN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) to give the title compound (140 mg, 58%) as a palesolid; NMR spectrum (CDCl₃) 2.16-2.03 (m, 4H), 2.29 (s, 3H), 2.34 (s,6H), 2.53 (s, 3H), 3.07 (d, 1H), 3.14 (d, 1H), 3.60 (m, 2H), 4.06 (t,1H), 4.62 (m, 1H), 4.68 (m, 1H), 6.91 (d, 1H), 7.14-7.07 (m, 3H), 7.47(m, 2H), 7.64 (m, 2H), 8.27 (s, 1H), 8.62 (s, 1H), 9.80 (s br, 1H); Massspectrum: MH⁺ 527.

EXAMPLE 592-(4-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenoland 2-picolyl chloride hydrochloride to give the title compound in 32%yield; NMR spectrum (DMSO-d6) 1.25-1.40 (m, 2H), 1.87 (m, 2H), 2.35 (m,1H), 2.73 (m, 1H), 3.05 (m, 1H), 3.75 (m, 1H), 4.09 (dd, 2H), 4.24 (d,2H), 4.44 (m, 1H), 4.47 (t, 1H), 5.30 (s, 2H), 7.17 (d, 1H), 7.28 (d,1H), 7.36 (d, 1H), 7.37 (dd, 1H), 7.47 (dd, 1H), 7.59 (d, 1H), 7.74 (dd,1H), 7.89 (ddd, 1H), 8.19 (d, 1H), 8.55 (s, 1H), 8.60 (d, 1H), 9.94 (s,1H); Mass spectrum MH⁺ 534.4, 536.4.

The2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenolused as starting material was obtained as follows:

Sodium hydride (60% dispersion in mineral oil, 864 mg, 21.6 mmol) wassuspended in DMA (40 ml), and 4-(hydroxymethyl)piperidine (2.48 g, 21.6mmol) was added dropwise as a solution in DMA (20 ml) under a nitrogenatmosphere. The mixture was stirred for 20 minutes at ambienttemperature, and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol(obtained as described in example 21, preparation of starting materials,2.50 g, 8.65 mmol) was added. The mixture was heated to 110° C. for 5hours under a nitrogen atmosphere, and then cooled to ambienttemperature. Saturated ammonium chloride solution (10 ml) was added, andthe mixture concentrated in vacuo. The residue was treated withsaturated sodium hydrogen carbonate solution (75 ml), and the mixturestirred and sonicated to give a granular precipitate. The solid wascollected by filtration, washed with water, and dried to give2-chloro-4-{[5-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}phenol as acream coloured solid (3.35 g, quantitative); NMR spectrum (DMSO-d6) 1.32(m, 2H), 1.78 (m, 2H), 2.15 (m, 1H), 2.60 (m, 2H), 3.04 (m, 2H), 4.17(d, 2H), 7.00 (d, 1H), 7.14 (d, 1H), 7.34 (d, 1H), 7.48 (dd, 1H), 7.72(dd, 1H), 7.96 (d, 1H), 8.51 (s, 1H), 9.94 (s, 1H); Mass spectrum MH⁺385.0, 387.0.

HATU (1.09 g, 2.86 mmol) was added to a mixture of2-chloro-4-{[5-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}phenol (1.00g, 2.60 mmol) and glycolic acid (217 mg, 2.86 mmol) in DMA (30 ml). Themixture was stirred at ambient temperature for 16 hours, and thenconcentrated in vacuo. The residue was purified by chromatography,eluting with 4 to 6% (10:1 MeOH/conc. NH_(3(aq))) in DCM to give2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenolas a yellow solid (810 mg, 70%); NMR spectrum (DMSO-d6) 1.25-1.40 (m,2H), 1.86 (m, 2H), 2.34 (m, 1H), 2.74 (m, 1H), 3.05 (m, 1H), 3.75 (m,1H), 4.08 (s, 2H), 4.23 (d, 2H), 4.42 (t, 1H), 4.42 (m, 1H), 7.01 (d,1H), 7.16 (d, 1H), 7.33 (dd, 1H), 7.34 (d, 1H), 7.73 (dd, 1H), 8.04 (d,1H), 8.51 (s, 1H), 9.87 (s, 1H), 10.05 (br.s, 1H); Mass spectrum MH⁺443.0, 445.0.

EXAMPLE 602-(4-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 59, preparation of starting materials)and 4-(chloromethyl)-1,3-thiazole hydrochloride to give the titlecompound in 26% yield; NMR spectrum (DMSO-d6); 1.25-1.45 (m, 2H), 1.87(m, 2H), 2.36 (m, 1H), 2.73 (m, 1H), 3.05 (m, 1H), 3.76 (m, 1H), 4.10(dd, 2H), 4.24 (d, 2H), 4.43 (m, 1H), 4.49 (t, 1H), 5.34 (s, 2H), 7.17(d, 1H), 7.36 (d, 1H), 7.36 (d, 1H), 7.48 (dd, 1H), 7.75 (dd, 1H), 7.83(d, 1H), 8.17 (d, 1H), 8.55 (s, 1H), 9.15 (d, 1H), 9.95 (s, 1H); Massspectrum MH⁺ 540.4, 542.4.

EXAMPLE 612-(4-{[(4-{[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

Methanesulfonyl chloride (19 μl, 0.25 mmol) was added to a solution of1,3-thiazol-2-ylmethanol (29 mg, 0.25 mmol) andN,N-diisopropylethylamine (44 μl, 0.25 mmol) in DCM (5 ml) at 0° C. Themixture was allowed to warm to ambient temperature, stirred for 2 hoursand concentrated in vacuo. The residue was dissolved in DMA (5 ml), andadded to a suspension of2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 59, preparation of starting materials,89 mg, 0.20 mmol) and potassium carbonate (138 mg, 1.00 mmol) in DMA (5ml). The mixture was stirred at room temperature for 16 hours, thenconcentrated in vacuo. The residue was partitioned between DCM (15 ml)and water (15 ml). The DCM fraction was loaded onto a silica column,which was eluted with 2 to 4% (10:1 MeOH/conc. NH_(3(aq))) in DCM. Theappropriate fractions were concentrated and the residue crystallisedtwice from ethyl acetate to give the title product as a white solid (30mg, 28%); NMR spectrum (DMSO-d6) 1.25-1.45 (m, 2H), 1.87 (m, 2H), 2.36(m, 1H), 2.73 (m, 1H), 3.05 (m, 1H), 3.75 (m, 1H), 4.09 (dd, 2H), 4.24(d, 2H), 4.43 (m, 1H), 4.48 (t, 1H), 5.56 (s, 2H), 7.17 (d, 1H), 7.35(d, 1H), 7.37 (d, 1H), 7.50 (dd, 1H), 7.75 (dd, 1H), 7.81 (d, 1H), 7.87(d, 1H), 8.20 (d, 1H), 8.56 (s, 1H), 9.96 (s, 1H); Mass spectrum MH⁺540.2, 542.2.

EXAMPLE 622-[4-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 59, preparation of starting materials)and 3-fluorobenzyl chloride to give the title, compound in 46% yield;NMR spectrum (DMSO-d6) 1.25-1.45 (m, 2H), 1.87 (m, 2H), 2.35 (m, 1H),2.73 (m, 1H), 3.05 (m, 1H), 3.76 (m, 1H), 4.09 (dd, 2H), 4.24 (d, 2H),4.43 (m, 1H), 4.48 (t, 1H), 5.26 (s, 2H), 7.17 (d, 1H), 7.18 (ddd, 1H),7.27 (d, 1H), 7.30-7.35 (m, 2H), 7.36 (d, 1H), 7.47 (dd, 1H), 7.48 (ddd,1H), 7.75 (dd, 1H), 8.18 (d, 1H), 8.55 (s, 1H), 9.94 (s, 1H); Massspectrum MH⁺ 551.2, 553.2

EXAMPLE 632-[4-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

Methanesulfonyl chloride (19 μl, 0.25 mmol) was added to a solution of6-methylpyridin-2-ylmethanol (31 mg, 0.25 mmol) andN,N-diisopropylethylamine (44 μl, 0.25 mmol) in DCM (5 ml) at 0° C. Themixture was allowed to warm to ambient temperature, was stirred for 2hours and concentrated in vacuo. The residue was dissolved in DMA (5ml), and added to a suspension of2-chloro-4-({5-[(1-glycoloylpiperidin-4-yl)methoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 59, preparation of starting materials,89 mg, 0.20 mmol) and potassium carbonate (138 mg, 1.00 mmol) in DMA (5ml). The mixture was stirred at room temperature for 16 hours, thenconcentrated in vacuo. The residue was partitioned between DCM (15 ml)and water (15 ml). The DCM fraction was loaded onto a silica column,which was purified by chromatography, eluting with 2 to 4.5% (10:1MeOH/conc. NH_(3(aq))) in DCM. The appropriate fractions wereconcentrated in vacuo and the residue purified by reverse phase HPLC,eluting with 5 to 50% MeCN in water containing 0.2% TFA. The appropriatefractions were basified with 2N sodium hydroxide solution (1 ml), andextracted with DCM (2×15 ml). The combined extractions were filteredthrough a silicone-treated filter paper and concentrated in vacuo. Theresidue was crystallised from ethyl acetate/iso-hexane to give the titlecompound as a white solid (20 mg, 18%); NMR spectrum (DMSO-d6) 1.25-1.40(m, 2H), 1.87 (m, 2H), 2.36 (m, 1H), 2.51 (s, 3H), 2.73 (m, 1H), 3.05(m, 1H), 3.76 (m, 1H), 4.09 (dd, 2H), 4.24 (d, 2H), 4.43 (m, 1H), 4.47(t, 1H), 5.25 (s, 2H), 7.17 (d, 1H), 7.22 (d, 1H), 7.27 (d, 1H), 7.36(d, 1H), 7.37 (d, 1H), 7.47 (dd, 1H), 7.75 (dd, 1H), 7.77 (dd, 1H), 8.19(d, 1H), 8.55 (s, 1H), 9.95 (s, 1H); Mass spectrum MH⁺ 548.4, 550.4.

EXAMPLE 642-((2S)-2-{[(4-{[3-methyl-pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenoland 2-picolyl chloride hydrochloride to give the title compound as awhite solid in 15% yield; NMR spectrum (DMSO) 1.98 (m, 4H), 2.27 (s,3H), 3.38 (m, 2H), 4.02 (m, 2H), 4.21 (dd, 1H), 4.43 (dd, 1H), 4.55 (m,2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.22 (d, 1H), 7.29 (d, 1H), 7.33 (dd,1H), 7.50 (m, 3H), 7.68 (t, 1H), 7.85 (td, 1H), 8.41 (s, 1H), 8.57 (d,1H), 9.84 (s, 1H); Mass spectrum MH⁺ 500.

The4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-({5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenoland glycolic acid in 88% yield; NMR spectrum (DMSO) 1.96 (m, 4H), 2.16(s, 3H), 3.33 (m, 2H), 4.01 (d, 2H), 4.29 (m, 1H), 4.46 (dd, 1H), 4.57(m, 1H), 6.83 (d, 1H), 7.23 (d, 1H), 7.31 (m, 2H), 7.50 (d, 1H), 7.94(t, 1H), 8.72 (s, 1H), 9.53 (s, 1H), 10.91 (s, 1H); Mass spectrum MH⁺409.

The2-methyl-4-({5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol and D-prolinol in 92%yield; NMR spectrum (DMSO) 1.49 (m, 1H), 1.66 (m, 2H), 1.85 (m, 1H),2.16 (s, 3H), 2.83 (t, 2H), 3.57 (m, 1H), 4.05 (dd, 1H), 4.26 (dd, 1H),6.77 (d, 1H), 7.09 (d, 1H), 7.27 (d, 1H), 7.49 (m, 2H), 7.66 (t, 1H),8.39 (s, 1H), 10.31 (s, 1H); Mass spectrum MH⁺ 351.

The 2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol used as startingmaterial was prepared as described in example 21 (preparation ofstarting materials) using 4-chloro-5-fluoroquinazoline (prepared asdescribed in example 1, preparation of starting materials) and4-amino-2-methyl-phenol in 82% yield; NMR spectrum (DMSO-d6) 3.30 (s,3H), 6.78 (d, 1H), 7.28 (m, 2H), 7.38 (dd, 1H), 7.57 (d, 1H), 7.78 (m,1H), 8.43 (s, 1H), 8.88 (d, 1H), 9.22 (s, 1H); Mass spectrum MH⁺ 270.

EXAMPLE 652-(2S)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 25 was repeated using4-[(5-{[(2S)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenol(obtained as described in example 64, preparation of starting materials)and pyrazin-2-ylmethanol to give the title compound as a pale yellowsolid in 25% yield; NMR spectrum (DMSO) 1.96 (m, 4H), 2.24 (s, 3H), 3.37(m, 2H), 3.98 (m, 2H), 4.18 (dd, 1H), 4.42 (dd, 1H), 4.49 (m, 2H), 5.25(s, 2H), 7.03 (d, 1H), 7.20 (d, 1H), 7.27 (d, 1H), 7.46 (m, 2H), 7.67(t, 1H), 8.39 (s, 1H), 8.61 (d, 1H), 8.65 (d, 1H), 8.82 (s, 1H), 9.83(s, 1H); Mass spectrum MH⁺ 501.

EXAMPLE 662-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenoland 2-picolyl chloride hydrochloride to give the title compound as ayellow solid in 35% yield; NMR spectrum (DMSO) 1.98 (m, 4H), 2.27 (s,3H), 3.38 (m, 2H), 4.02 (m, 2H), 4.21 (dd, 1H), 4.43 (dd, 1H), 4.55 (m,2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.22 (d, 1H), 7.29 (d, 1H), 7.33 (dd,1H), 7.50 (m, 3H), 7.68 (t, 1H), 7.85 (td, 1H), 8.41 (s, 1H), 8.57 (d,1H), 9.84 (s, 1H); Mass spectrum MH⁺ 500.

The4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-({5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenoland glycolic acid in 95% yield; NMR spectrum (DMSO) 1.96 (m, 4H), 2.16(s, 3H), 3.33 (m, 2H), 4.01 (d, 2H), 4.29 (m, 1H), 4.46 (dd, 1H), 4.57(m, 1H), 6.83 (d, 1H), 7.23 (d, 1H), 7.31 (n, 2H), 7.50 (d, 1H), 7.94(t, 1H), 8.72 (s, 1H), 9.53 (s, 1H), 10.91 (s, 1H); Mass spectrum MH⁺409.

The2-methyl-4-({5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol (prepared as describedin example 64, preparation of starting materials) and L-prolinol in 20%yield; NMR spectrum (DMSO) 1.49 (m, 1H), 1.66 (m, 2H), 1.85 (m, 1F),2.16 (s, 3H), 2.83 (t, 2H), 3.57 (m, 1H), 4.05 (dd, 1H), 4.26 (dd, 1H),6.77 (d, 1H), 7.09 (d, 1H), 7.27 (d, 1H), 7.49 (m, 2H), 7.66 (t, 1H),8.39 (s, 1H), 10.31 (s, 1H); Mass spectrum MH⁺ 351.

EXAMPLE 672-((2R)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 25 was repeated using4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenol(obtained as described in example 66, preparation of starting materials)and pyrazin-2-ylmethanol to give the title compound as a white solid in38% yield; NMR spectrum (DMSO) 1.96 (m, 4H), 2.24 (s, 3H), 3.37 (m, 2H),3.98 (m, 2H), 4.18 (dd, 1H), 4.42 (dd, 1H), 4.49 (m, 2H), 5.25 (s, 2H),7.03 (d, 1H), 7.20 (d, 1H), 7.27 (d, 1H), 7.46 (m, 2H), 7.67 (t, 1H),8.39 (s, 1H), 8.61 (d, 1H), 8.65 (d, 1H), 8.82 (s, 1H), 9.83 (s, 1H);Mass spectrum MH⁺ 501.

EXAMPLE 682-((2R)-2-{[(4-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using4[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenol(obtained as described in example 66, preparation of starting materials)and 4-(chloromethyl)thiazole hydrochloride to give the title compound asa yellow solid in 29% yield; NMR spectrum (DMSO) 1.99 (m, 4H), 2.21 (s,3H), 3.37 (m, 2H), 4.02 (m, 2H), 4.21 (dd, 1H), 4.43 (dd, 1H), 4.55 (m,2H), 5.24 (s, 2H), 7.09 (d, 1H), 7.24 (d, 1H), 7.32 (d, 1H), 7.47 (m,2H), 7.67 (t, 1H), 7.77 (d, 1H), 8.41 (s, 1H), 9.13 (d, 1H), 9.84 (s,1H); Mass spectrum MH⁺ 506.

EXAMPLE 692-[(2R)-2-({[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure described in example 21 was repeated using4-[(5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenol(obtained as described in example 66, preparation of starting materials)and 3-(chloromethyl)-5-methylisoxazole to give the title compound as apale yellow solid in 45% yield; NMR spectrum (DMSO) 1.98 (m, 4H), 2.19(s, 3H), 2.41 (s, 3H), 3.37 (m, 2H), 4.02 (m, 2H), 4.19 (dd, 1H), 4.45(dd, 1H), 4.56 (m, 2H), 5.16 (s, 2H), 6.35 (s, 1H), 7.06 (d, 1H), 7.24(d, 1H), 7.31 (d, 1H), 7.47 (m, 2H), 7.68 (t, 1H), 8.42 (s, 1H), 9.84(s, 1H); Mass spectrum MH⁺ 504.

EXAMPLE 705-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-{3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}quinazolin-4-amine

The procedure described in example 21 was repeated using4-[(5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinolin-4-yl)amino]-2-methylphenoland 3-(chloromethyl)-5-methylisoxazole to give the title compound as awhite solid in 30% yield; NMR spectrum (DMSO) 1.98 (m, 4H), 2.18 (s,3H), 2.42 (s, 3H), 3.26 (s, 3H), 3.41 (m, 2H), 4.01 (s, 2H), 4.18 (dd,1H), 4.44 (dd, 1H), 4.55 (m, 1H), 5.16 (s, 2H), 6.35 (s, 1H), 7.05 (d,1H), 7.22 (d, 1H), 7.32 (d, 1H), 7.49 (m, 2H), 7.67 (t, 1H), 8.41 (s,1H), 9.83 (s, 1H); Mass spectrum MH⁺ 518.

The4-[(5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-({5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 66, preparation of starting materials)and methoxyacetic acid in 100% yield; NMR spectrum (DMSO) 1.93 (m, 4H),2.17 (s, 3H), 3.24 (s, 3H), 3.41 (m, 2H), 3.98 (d, 1H), 4.02 (d, 1H),4.27 (dd, 1H), 4.45 (dd, 1H), 4.57 (m, 1H), 6.82 (d, 1H), 7.24 (dd, 1H),7.33 (m, 2H), 7.48 (d, 1H), 7.96 (t, 1H), 8.73 (s, 1H), 9.53 (s, 1H),10.99 (s, 1H); Mass spectrum MH⁺ 422.

EXAMPLE 715-{[(2R)-4-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine

The procedure described in example 21 was repeated using4-[(5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenol(obtained as described in example 70, preparation of starting materials)and 2-picolyl chloride hydrochloride to give the title compound as ayellow solid in 31% yield; NMR spectrum (DMSO) 1.98 (m, 4H), 2.26 (s,3H), 3.25 (s, 3H), 3.40 (m, 2H), 4.02 (s, 2H), 4.18 (dd, 1H), 4.43 (dd,1H), 4.56 (m, 1H), 5.20 (s, 2H), 7.00 (d, 1H), 7.21 (d, 1H), 7.30 (d,1H), 7.34 (dd, 1H), 7.53 (m, 3H), 7.67 (t, 1H), 7.86 (td, 1H), 8.40 (s,1H), 8.58 (d, 1H), 9.85 (s, 1H); Mass spectrum MH⁺ 514.

EXAMPLE 725-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine

The procedure described in example 21 was repeated using4-[(5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenol(obtained as described in example 70, preparation of starting materials)and 4-(chloromethyl)thiazole hydrochloride to give the title compound asa white solid in 27% yield; NMR spectrum (DMSO) 1.99 (m, 4H), 2.22 (s,3H), 3.24 (s, 3H), 3.42 (m, 2H), 4.01 (s, 2H), 4.20 (dd, 1H), 4.42 (dd,1H), 4.55 (m, 1H), 5.25 (s, 2H), 7.10 (d, 1H), 7.22 (d, 1H), 7.32 (d,1H), 7.49 (m, 2H), 7.70 (t, 1H), 7.78 (d, 1H), 8.42 (s, 1H), 9.14 (d,1H), 9.87 (s, 1H); Mass spectrum MH⁺ 520.

EXAMPLE 732-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 21 was repeated using4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenoland 2-picolyl chloride hydrochloride to give the title compound as awhite solid in 44% yield; NMR spectrum (DMSO-d6, 100° C.) 1.45 (m, 1H),1.67 (m, 4H), 1.87 (m, 1H), 2.26 (s, 3H), 3.17 (m, 1H), 3.82 (m, 1H),4.05 (m, 2H), 4.47 (dd, 1H), 4.63 (dd, 1H), 4.95 (m, 1H), 5.20 (s, 2H),7.01 (d, 1H), 7.23 (d, 1H), 7.34 (m, 2H), 7.47 (m, 2H), 7.55 (d, 1H),7.67 (t, 1H), 7.83 (td, 1H), 8.40 (s, 1H), 8.57 (d, 1H), 9.57 (s, 1H);Mass spectrum MH⁺ 514.

The4-[(5-{[(2R)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]-2-methylphenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-({5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenoland glycolic acid in 40% yield; NMR spectrum (DMSO-d6, 100° C.); 1.45(m, 1H), 1.66 (m, 4H), 1.86 (m, 1H), 2.17 (s, 3H), 3.10 (m, 1H), 3.80(m, 1H), 4.04 (m, 2H), 4.46 (dd, 1H), 4.60 (dd, 1H), 4.94 (m, 1H), 6.77(d, 1H), 7.21 (d, 1H), 7.31 (m, 3H), 7.66 (t, 1H), 8.37 (s, 1H), 8.77(s, 1H), 9.47 (s, 1H); Mass spectrum MH⁺ 423.

The2-methyl-4-({5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolused as starting material was prepared as described in example 21(preparation of starting materials) using2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol (prepared as describedin example 64, preparation of starting materials) and(2R)-piperidin-2-ylmethanol (prepared as described in example 7,preparation of starting materials) in 99% yield; NMR spectrum (DMSO)1.30 (m, 3H), 1.48 (br d, 1H), 1.62 (br d, 1H), 1.77 (br d, 1H), 2.16(s, 3H), 3.10 (m, 1H), 2.61 (br t, 1H), 3.00 (m, 2H), 4.11 (dd, 1H),4.23 (dd, 1H), 6.75 (d, 1H), 7.04 (d, 1H), 7.26 (d, 1H), 7.48 (d, 1H),7.62 (dd, 1H), 7.66 (t, 1H), 8.41 (s, 1H), 9.16 (s, 1H), 10.40 (s, 1H);Mass spectrum MH⁺ 365.

EXAMPLE 742-(3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

HATU (121 mg, 0.32 mmol) was added to a solution ofN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-amine(150 mg, 0.316 mmol) and glycolic acid (26 mg, 0.32 mmol) in dry DMF (5ml). The reaction was stirred at ambient temperature for 2 days. Thereaction mixture was concentrated and the residue was stirred in water.The resultant precipitate was filtered and purified by chromatographyeluting with 3-10% (10:1 MeOH/conc. NH_(3 (aq))) in DCM to give a gum.This was triturated with ether to give the title compound as a solid (95mg, 57%); NMR spectrum (DMSO-d6, 373K) 1.45-1.58 (m, 2H), 1.68-1.79 (m,1H), 1.93-2.03 (m, 1H), 2.20-2.34 (m, 1H), 3.00-3.16 (m, 2H), 3.67-3.90(m, 1H), 4.00-4.20 (m, 3H), 4.23-4.39 (m, 2H), 5.28 (s, 2H), 7.16 (d,1H), 7.25 (d, 1H), 7.29-7.41 (m, 2H), 7.54-7.64 (m, 2H), 7.71 (t, 1H),7.85 (t, 1H), 8.04 (s, 1H), 8.52 (s, 1H), 8.58 (d, 1H), 9.79 (s, 1H);Mass spectrum MH⁺ 534.

The startingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as follows:

tert-Butyl(3R)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine-1-carboxylatewas prepared as described in example 21 (preparation of startingmaterials) usingtert-butyl(3R)-3-(hydroxymethyl)piperidine-1-carboxylate and2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol in quantitative yield;NMR spectrum (CDCl₃) 0.74-0.85 (m, 1H), 1.13-1.60 (m, 11H), 1.62-1.76(m, 1H), 1.88-2.01 (m, 1H), 2.10-2.26 (m, 1H), 2.86-3.10 (m, 2H),3.67-3.80 (m, 1H), 3.91-4.19 (m, 3H), 6.84 (d, 1H), 6.97 (d, 1H),7.25-7.37 (m, 1H), 7.51 (d, 1H), 7.59 (t, 1H), 7.88 (d, 1H), 8.55 (s,1H), 9.83 (s, 1H); Mass spectrum MH⁺ 485.

tert-Butyl(3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatewas prepared as described in example 21 (preparation of startingmaterials) usingtert-butyl(3R)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine-1-carboxylateand 2-picolyl chloride hydrochloride in 76% yield; NMR spectrum (CDCl₃300 MHz) 1.14-1.59 (m, 10H), 1.60-1.82 (m, 2H), 1.90-2.02 (m, 1H), 2.112.26 (m, 1H), 2.86-3.08 (m, 2H), 3.68-3.82 (m, 1H), 3.95-4.17 (m, 3H),5.22 (s, 2H), 6.81 (d, 1H), 6.94 (d, 1H), 7.13-7.18 (m, 1H), 7.39-7.50(m, 2H), 7.52-7.62 (m, 2H), 7.64-7.73 (m, 1H), 7.90 (d, 1H), 8.52 (d,1H), 8.56 (s, 1H), 9.74 (s, 1H); Mass spectrum MH⁺ 576.

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as described in example 29 (preparation of startingmaterials) usingtert-butyl(3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatein 82% yield); NMR spectrum (DMSO-d6) 1.30-1.42 (m, 1H), 1.47-1.76 (m,1H), 1.68-1.78 (m, 1H), 1.88-1.97 (m, 1H), 2.24-2.36 (m, 1H), 2.58-2.70(m, 2H), 3.04 (d, 2H, partially obscured by DMSO), 4.21-4.31 (m, 2H),5.31 (s, 2H), 7.18 (d, 1H), 7.28 (d, 1H), 7.34-7.40 (m, 2H), 7.54-7.61(m, 2H), 7.75 (t, 1H) 7.86-7.93 (m, 1H), 8.10-8.14 (m, 1H), 8.54 (s,1H), 8.61 (d, 1H), 9.92 (s, 1H); Mass spectrum MH⁺ 476.

EXAMPLE 752-((3R)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 74 was repeated usingN-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-amineand glycolic acid to give the title compound in 35% yield; NMR spectrum(DMSO-d6 373K) 1.46-1.62 (m, 2H), 1.71-1.83 (m, 1H), 1.96-2.03 (m, 1H),2.22-2.34 (m, 1H), 3.00-3.14 (m, 2H), 3.68-3.91 (m, 1H), 4.00-4.19 (m,3H), 4.25-4.40 (m, 2H), 5.32 (s, 2H), 7.19 (d, 1H), 7.32 (d, 1H), 7.39(d, 1H), 7.63 (d, 1H), 7.69-7.80 (m, 2H), 8.03 (s, 1H), 8.37 (s, 1H),9.08 (s, 1H), 9.80 (s, 1H); Mass spectrum MH⁺ 540.

The startingN-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as follows:

tert-Butyl(3R)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatewas prepared as described in example 21 (preparation of startingmaterials) usingtert-butyl(3R)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine-1-carboxylate(obtained as described in example 74, preparation of starting materials)and 4-(chloromethyl)-1,3-thiazole hydrochloride in 87% yield; NMRspectrum (CDCl₃) 1.14-1.60 (m, 10H), 1.61-1.81 (m, 2H), 1.91-2.04 (m,1H), 2.11 2.27 (m, 1H), 2.87-3.12 (m, 2H), 3.68-3.83 (m, 1H), 3.92-4.19(m, 3H), 5.29 (s, 2H), 6.82 (d, 1H), 6.99 (d, 1H), 7.38-7.53 (m, 3H),7.57 (t, 1H), 7.89 (d, 1H), 8.57 (d, 1H), 8.77 (d, 1H), 9.76 (s, 1H);Mass spectrum MH⁺ 582.

N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as described in example 29 (preparation of startingmaterials) usingtert-butyl(3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatein 91% yield; NMR spectrum (DMSO-d6) 1.32-1.47 (m, 1H), 1.53-1.69 (m,1H), 1.73-1.84 (m, 1H), 1.89-2.01 (m, 1H), 2.31-2.44 (m, 1H), 2.72 (q,2H), 3.13 (d, 1H), 3.30 (d, 1H), 4.22-4.36 (m, 2H), 5.35 (s, 2H), 7.18(d, 1H), 7.32-7.44 (m, 1H), 7.59 (dd, 1H), 7.75 (t, 1H), 7.82 (s, 1H),8.07 (dd, 1H), 8.54 (s, 1H), 9.16 (dd, 1H), 9.87 (s, 1H); Mass spectrumMH⁺ 482.

EXAMPLE 762-[(3R)-3-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure described in example 74 was repeated usingN-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-amineand glycolic acid to give the title compound in 44% yield; NMR spectrum(DMSO-d6, 373K) 1.45-1.60 (in 2H), 1.71-1.81 (m, 1H), 1.94-2.04 (m, 1H),2.21-2.33 (m, 1H), 2.43 (s, 3H), 3.00-3.14 (m, 2H), 3.71-3.88 (m, 1H),4.00-4.18 (m, 3H), 4.24-4.37 (m, 2H), 5.21 (s, 2H), 6.31 (s, 1H), 7.16(d, 1H), 7.27 (d, 1H), 7.37 (d, 1H), 7.61 (d, 1H), 7.71 (t, 1H), 8.04(s, 1H), 8.51 (s, 1H), 8.81 (s, 1H); Mass spectrum MH⁺ 538.

The startingN-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as follows:

tert-Butyl(3R)-3-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidine-1-carboxylatewas prepared as described in example 21 (preparation of startingmaterials) usingtert-butyl(3R)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine1-carboxylate (obtained as described in example 74, preparation ofstarting materials) and 3-(chloromethyl)-5-methylisoxazole in 90% yield;NMR spectrum (CDCl₃ 300 MHz) 1.14-1.59 (m, 10H), 1.60-1.81 (m, 2H),1.90-2.03 (m, 1H), 2.11-2.24 (m, 1H), 2.37 (s, 3H), 2.86-3.11 (m, 2H),3.68-3.82 (m, 1H), 3.94-4.17 (m, 3H), 5.12 (s, 2H), 6.12 (s, 1H), 6.81(d, 1H), 6.98 (d, 1H), 7.37-7.50 (m, 2H), 7.57 (t, 1H), 7.91 (d, 1H),8.56 (s, 1H), 9.75 (s, 1H); Mass spectrum MH⁺ 580.

N-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as described in example 29 (preparation of startingmaterials) usingtert-butyl(3R)-3-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidine-1-carboxylatein 91% yield; NMR spectrum (DMSO-d6) 1.32-1.47 (m, 1H), 1.56-1.72 (m,1H), 1.76-1.87 (m, 1H), 1.90-2.02 (m, 1H), 2.44 (s, 3H), 2.67-2.85 (m,2H), 3.18 (d, 1H), 3.33 (d, 1H), 4.23-4.37 (m, 2H), 5.28 (s, 2H), 6.36(s, 1H), 7.19 (d, 1H), 7.76 (t, 1H), 8.09 (d, 1H), 8.54 (s, 1H), 9.85(s, 1H); Mass spectrum MH⁺ 480.

EXAMPLE 772-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 74 was repeated using ofN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-ylmethoxy]quinazolin-4-amineand glycolic acid to give the title compound in 60% yield; NMR spectrum(DMSO-d6, 373K) 1.45-1.58 (m, 2H), 1.68-1.79 (m, 1H), 1.93-2.03 (m, 1H),2.20-2.34 (m, 1H), 3.00-3.16 (m, 2H), 3.67-3.90 (m, 1H), 4.00-4.20 (m,3H), 4.23-4.39 (m, 2H), 5.28 (s, 2H), 7.16 (d, 1H), 7.25 (d, 1H),7.29-7.41 (m, 2H), 7.54-7.64 (m, 2H), 7.71 (t, 1H), 7.85 (t, 1H), 8.04(s, 1H), 8.52 (s, 1H), 8.58 (d, 1H), 9.79 (s, 1H); Mass spectrum MH⁺534.

The startingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as follows:

tert-Butyl(3S)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine-1-carboxylateused was prepared as described in example 21 (preparation of startingmaterials) usingtert-butyl(3S)-3-(hydroxymethyl)piperidine-1-carboxylate and2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol in quantitative yield;NMR spectrum (CDCl₃) 0.74-0.85 (m, 1H), 1.13-1.60 (m, 11H), 1.62-1.76(m, 1H), 1.88-2.01 (m, 1H), 2.10-2.26 (m, 1H), 2.86-3.10 (m, 2H),3.67-3.80 (m, 1H), 3.91-4.19 (m, 3H), 6.84 (d, 1H), 6.97 (d, 1H),7.25-7.37 (m, 1H), 7.51 (d, 1H), 7.59 (t, 1H), 7.88 (d, 1H), 8.55 (s,1H), 9.83 (s, 1H); Mass spectrum MH⁺ 485.

tert-Butyl(3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatewas prepared as described in example 21 (preparation-of-startingmaterials) usingtert-butyl(3S)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine-1-carboxylateand 2-picolyl chloride hydrochloride in 76% yield; NMR spectrum (CDCl₃)1.14-1.59 (m, 10H), 1.60-1.82 (m, 2H), 1.90-2.02 (m, 1H), 2.11 2.26 (m,1H), 2.86-3.08 (m, 2H), 3.68-3.82 (m, 1H), 3.95-4.17 (m, 3H), 5.22 (s,2H), 6.81 (d, 1H), 6.94 (d, 1H), 7.13-7.18 (m, 1H), 7.39-7.50 (m, 2H),7.52-7.62 (m, 2H), 7.64-7.73 (m, 1H), 7.90 (d, 1H), 8.52 (d, 1H), 8.56(s, 1H), 9.74 (s, 1H); Mass spectrum MH⁺ 576.

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as described in example 29 (preparation of startingmaterials) usingtert-butyl(3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatein 82% yield; NMR spectrum (DMSO-d6) 1.30-1.42 (m, 1H), 1.47-1.76 (m,1H), 1.68-1.78 (m, 1H), 1.88-1.97 (m, 1H), 2.24-2.36 (m, 1H), 2.58-2.70(m, 2H), 3.04 (d, 2H, partially obscured by DMSO), 4.21-4.31 (m, 2H),5.31 (s, 2H), 7.18 (d, 1H), 7.28 (d, 1H), 7.34-7.40 (m, 2H), 7.54-7.61(m, 2H), 7.75 (t, 1H) 7.86-7.93 (m, 1H), 8.10-8.14 (m, 1H), 8.54 (s,1H), 8.61 (d, 1H), 9.92 (s, 1H); Mass spectrum MH⁺ 476.

EXAMPLE 782-((3S)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol

The procedure described in example 74 was repeated usingN-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-ylmethoxy]quinazolin-4-amineand glycolic acid to give the title compound in 35% yield; NMR spectrum(DMSO-d6 373K) 1.46-1.62 (m, 2H), 1.71-1.83 (m, 1H), 1.96-2.03 (m, 1H),2.22-2.34 (m, 1H), 3.00-3.14 (m, 2H), 3.68-3.91 (m, 1H), 4.00-4.19 (m,3H), 4.25-4.40 (m, 2H), 5.32 (s, 2H), 7.19 (d, 1H), 7.32 (d, 1H), 7.39(d, 1H), 7.63 (d, 1H), 7.69-7.80 (m, 2H), 8.03 (s, 1H), 8.37 (s, 1H),9.08 (s, 1H), 9.80 (s, 1H); Mass spectrum MH⁺ 540.

The startingN-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-[(3R)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as follows:

tert-Butyl(3S)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatewas prepared as described in example 21 (preparation of startingmaterials) usingtert-butyl(3S)-3-[({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)methyl]piperidine-1-carboxylate(obtained as described in example 77, preparation of starting materials)and 4-(chloromethyl)-1,3-thiazole hydrochloride in 87% yield, NMRspectrum (CDCl₃) 1.14-1.60 (m, 10H), 1.61-1.81 (m, 2H), 1.91-2.04 (m,1H), 2.11 2.27 (m, 1H), 2.87-3.12 (m, 2H), 3.68-3.83 (m, 1H), 3.92-4.19(m, 3H), 5.29 (s, 2H), 6.82 (d, 1H), 6.99 (d, 1H), 7.38-7.53 (m, 3H),7.57 (t, 1H), 7.89 (d, 1H), 8.57 (d, 1H), 8.77 (d, 1H), 9.76 (s, 1H);Mass spectrum MH⁺ 582.

N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-[(3S)-piperidin-3-ylmethoxy]quinazolin-4-aminewas prepared as described in example 29 (preparation of startingmaterials) usingtert-butyl(3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidine-1-carboxylatein 91% yield; NMR spectrum (DMSO-d6) 1.32-1.47 (m, 1H), 1.53-1.69 (m,1H), 1.73-1.84 (m, 1H), 1.89-2.01 (m, 1H), 2.31-2.44 (m, 1H), 2.72 (q,2H), 3.13 (d, 1H), 3.30 (d, 1H), 4.22-4.36 (m, 2H), 5.35 (s, 2H), 7.18(d, 1H), 7.32-7.44 (m, 1H), 7.59 (dd, 1H), 7.75 (t, 1H), 7.82 (s, 1H),8.07 (dd, 1H), 8.54 (s, 1H), 9.16 (dd, 1H), 9.87 (s, 1H); Mass spectrumMH⁺ 482.

EXAMPLE 792-((3R)-3-{([(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-pyrrolidin-3-ylmethoxy]quinazolin-4-amine(150 mg, 0.33 mmol) and glycolic acid (31 mg, 0.41 mmol) were dissolvedin DMF (5 ml). HATU (149 mg, 0.42 mmol) was added and the resultingyellow solution stirred at 25° C. for 18 hours. The solvent was removedin vacuo, water (20 ml) and DCM (20 ml) were added. The suspension wassonicated before filtering the solid. This was washed well with waterand dried under vacuum to give the title compound as a yellow solid (160mg, 95% yield). NMR spectrum (DMSO-d6) 1.70-1.90 (m, 1H), 2.00-2.20 (m,1H), 2.90-3.00 (m, 1H), 3.30-3.60 (m, 4H), 4.00 (d, 2H), 4.40 (m, 2H),5.40 (s, 2H), 7.30-7.50 (m, 5H), 7.60 (d, 1H), 7.80-8.00 (m, 3H), 8.60(d, 1H), 8.80 (s, 1H), 10.66 (br s, 1H); Mass spectrum MH⁺ 520.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-pyrrolidin-3-ylmethoxy]quinazolin-4-amineused as starting material was prepared as follows:

Trifluoroacetic acid (10 ml) was added totert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.00 g)dissolved in DCM (10 ml). The resulting solution was stirred for 1 hourand the solvent removed in vacuo to give a pale brown oil. This wasdissolved in MeOH and MP-Carbonate resin (5.00 g) was added to give abasic methanolic solution. The mixture was stirred for 1 hour, filtered,the resin washed and the filtrate evaporated to give(3R)-pyrrolidin-3-ylmethanol as an orange oil (400 mg, 80%). NMRspectrum (DMSO-d6) 1.60 (m, 1H), 1.90 (m, 1H), 2.30 (m, 1H), 2.90 (m,1H), 3.00-3.40 (m, 5H), 4.80 (m, 1H), 8.80 (br s, 1H).

Sodium hydride (60% dispersion in mineral oil, 0.32 g) was added to(3R)-pyrrolidin-3-ylmethanol (0.33 g) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(obtained as described in example 1, preparation of starting materials,0.50 g) in DMA (4 ml) and the reaction heated at 120° C. for 4 hours.The reaction was cooled, quenched with water, and concentrated in vacuo.The residue was purified by chromatography using DCM—5% methanol/7Nammonia as eluent to giveN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-pyrrolidin-3-ylmethoxy]quinazolin-4-amineas a white solid (330 mg, 54%). NMR spectrum (DMSO-d6) 1.60 (m, 1H),1.90 (m, 1H), 2.70-3.00 (m, 5H), 4.20 (m, 1H), 5.30 (s, 2H), 7.10 (d,1H), 7.25 (d, 1H), 7.40 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (t,1H), 7.90 (t, 1H), 8.10 (m, 1H), 8.50 (s, 1H), 8.60 (d, 1H), 10.00 (brs, 1H); Mass spectrum M⁺ 462.

EXAMPLE 80N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-1-amine

The procedure described in example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-pyrrolidin-3-ylmethoxy]quinazolin-4-amine(60 mg, 0.13 mmol), HATU (64 mg, 0.17 mmol), and N,N-dimethylglycine(17.4 mg, 0.17 mmol) to give the title compound as a solid (51 mg, 79%).NMR spectrum (DMSO-d6) 1.80-2.00 (m, 1H), 2.00-2.25 (m, 1H), 2.75 (s,3H), 2.85 (s, 3H), 3.20-3.50 (m, 5H), 4.10 (d, 2H), 4.40 (d, 2H), 5.30(s, 2H), 7.30 (m, 2H), 7.35 (m, 2H), 7.50 (m, 2H), 7.70 (t, 2H), 8.00(m, 1H), 8.60 (d, 1H), 8.70 (d, 1H), 10.25 (br s, 1H); Mass spectrum MH⁺547.

EXAMPLE 81N-[3-chloro-4-pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine

The procedure described in example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-pyrrolidin-3-ylmethoxy]quinazolin-4-amine(60 mg, 0.13 mmol), HATU (64 mg, 0.17 mmol), and methoxyacetic acid (13ul, 0.17 mmol) to give the title compound as a solid (37 mg, 63%). NMRspectrum (DMSO-d6) 1.80-2.00 (m, 1H), 2.00-2.25 (m, 1H), 3.00 (m, 1H),3.30 (s, 3H), 3.30-3.60 (m, 4H), 3.80 (d, 2H), 4.40 (m, 2H), 5.40 (s,2H), 7.30-7.50 (m, 5H), 7.60 (d, 1H), 7.90 (m, 2H), 8.00 (t, 1H), 8.60(d, 1H), 8.90 (s, 1H), 10.70 (br s, 1H); Mass spectrum MH⁺ 534.

EXAMPLE 822-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure described in example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-pyrrolidin-3-ylmethoxy]quinazolin-4-amine(107 mg, 0.23 mmol), HATU (109 mg, 0.29 mmol), and glycolic acid (22 mg,0.29 mmol) to give the title compound as a solid (58 mg, 48%). NMRspectrum (DMSO-d6) 1.75-2.00 (m, 1H), 2.00-2.20 (m, 1H), 3.00 (m, 1H),3.30-3.70 (m, 4H), 4.00 (d, 2H), 4.40 (m, 2H), 5.40 (s, 2H), 7.30-7.50(m, 5H), 7.60 (d, 1H), 7.90 (m, 2H), 8.00 (t, 1H), 8.60 (d, 1H), 8.90(s, 1H), 10.70 (br s, 1H); Mass spectrum MH⁺ 520.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-pyrrolidin-3-ylmethoxy]quinazolin-4-amineused as starting material was prepared as follows:

Sodium hydride (60% dispersion in mineral oil, 0.48 g) was added to(3S)-pyrrolidin-3-ylmethanol (obtained as described for the R-antipodein example 79, preparation of starting materials, 0.50 g) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(0.75 g) in DMA (10 ml) and the reaction heated at 90° C. for 2 hours.The reaction was cooled, quenched with water, filtered and dried undervacuum to affordN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-pyrrolidin-3-ylmethoxy]quinazolin-4-amineas a white solid (910 mg, 100%). NMR spectrum (DMSO-d6) 1.60 (m, 1H),1.90 (m, 1H), 2.70-3.00 (m, 5H), 4.20 (d, 1H), 5.30 (s, 2H), 7.10 (d,1H), 7.25 (d, 1H), 7.40 (m, 2H), 7.50 (dd, 1H), 7.60 (d, 1H), 7.70 (t,1H), 7.90 (t, 1H), 8.10 (m, 1H), 8.50 (s, 1H), 8.60 (d, 1H), 10.00 (brs, 1H); Mass spectrum M⁺ 462.

EXAMPLE 83N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine

The procedure described in example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-pyrrolidin-3-ylmethoxy]quinazolin-4-amine(obtained as described in example 82, preparation of starting materials,107 mg, 0.23 mmol), HATU (109 mg, 0.29 mmol), and N,N-dimethylglycine(30 mg, 0.29 mmol) to give the title compound as a solid (64 mg, 50%).NMR spectrum (DMSO-d6) 1.75-2.00 (m, 1H), 2.00-2.20 (m, 1H), 2.80 (d,6H), 3.10 (m, 1H), 3.20-3.70 (m, 4H), 4.10 (d, 2H), 4.40 (m, 2H), 5.30(s, 2H), 7.30-7.40 (m, 4H), 7.50-7.60 (m, 2H), 7.80-8.00 (m, 3H), 8.60(d, 1H), 8.80 (s, 1H), 10.70 (br s, 1H) Mass spectrum MH⁺ 547.

EXAMPLE 84(N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3S)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine

The procedure described in Example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3S)-pyrrolidin-3-ylmethoxy]quinazolin-4-amine(obtained as described in example 82, preparation of starting materials,107 mg, 0.23 mmol), HATU (109 mg, 0.29 mmol), and 2-methoxyacetic acid(22 ul, 0.29 mmol) to give the title compound as a solid (85 mg, 69%).NMR spectrum (DMSO-d6) 1.70-2.00 (m, 1H), 2.00-2.20 (m, 1H), 2.90 (m,1H), 3.30 (s, 3H), 3.35-3.60 (m, 4H), 3.95 (d, 2H), 4.40 (m, 2H), 5.40(s, 2H), 7.30-7.50 (m, 5H), 7.60 (d, 1H), 7.90 (m, 2H), 8.00 (t, 1H),8.60 (d, 1H), 8.85 (s, 1H), 10.72 (br s, 1H); Mass spectrum MH⁺ 534.

EXAMPLE 85N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine

The procedure described in example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-morpholin-2-ylmethoxy]quinazolin-4-amine(100 mg, 0.21 mmol), HATU (104 mg, 0.28 mmol), and N,N-dimethylglycine(28 mg, 0.28 mmol) to give the title compound as a solid (48 mg, 41%);NMR spectrum (DMSO-d6) 2.80 (s, 6H), 3.20-3.80 (m, 4H), 3.90-4.20 (m,4H), 4.40 (m, 2H), 4.60 (m, 1H), 5.30 (s, 2H), 7.20-7.40 (m, 4H), 7.60(d, 1H), 7.70 (t, 1H), 7.80-8.00 (m, 3H), 8.60 (d, 1H), 8.80 (s, 1H),10.50-10.60 (br s, 1H); Mass spectrum MH⁺ 563

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-morpholin-2-ylmethoxy]quinazolin-4-amineused as starting material was prepared as follows:

Sodium hydride (60% dispersion in mineral oil, 1.01 g) was added to(2R)-morpholin-2-ylmethanol ((obtained as described in Journal ofMedicinal Chemistry 1998, 41(11), 1934-1942, 0.50 g) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine(1.00 g) in DMA (20 ml) and the reaction heated at 110° C. for 4 hours.The reaction was cooled, quenched with saturated NH₄Cl and filtered togive a solid. This was slurried in MeCN and stirred for 10 min. beforefiltration to giveN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-morpholin-2-ylmethoxy]quinazolin-4-amineas a yellow solid (585 mg, 46%). NMR spectrum (DMSO-d6) 2.50-2.80 (m,3H), 2.90 (d, 1H), 3.60 (dt, 1H), 3.80 (d, 1H), 4.20 (m, 1H), 4.20 (t,1H), 4.40 (dd, 1H), 5.30 (s, 2H), 7.10 (d, 1H), 7.25-7.40 (m, 3H), 7.60(d, 2H), 7.70 (m, 2H), 7.90 (t, 1H), 8.00 (d, 1H), 8.50 (s, 1H), 8.60(d, 1H), 10.25 (br s, 1H); Mass spectrum MH⁺ 478.

EXAMPLE 862-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol

The procedure described in example 79 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-morpholin-2-ylmethoxy]quinazolin-4-amine(obtained as described in example 85, preparation of starting materials,100 mg, 0.21 mmol), HATU (104 mg, 0.28 mmol), and glycolic acid (21 mg,0.28 mmol) to give the title compound as a solid (32 mg, 29%); NMRspectrum (DMSO-d6) 2.80 (m, 1H), 3.10 (m, 1H), 3.40 (m, 1H), 3.90-4.40(m, 6H), 4.50 (m, 1H), 4.60 (m, 1H), 5.30 (s, 2H), 7.10 (d, 1H), 7.30(d, 1H), 7.40 (d, 1H), 7.60 (d, 1H), 7.65-7.80 (m, 2H), 7.85 (t, 1H),8.00 (d, 1H), 8.60 (m, 2H), 10.18 (br s, 1H); Mass spectrum MH⁺ 536.

EXAMPLE 872-((2S)-2-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanoltrifluoroacetate

The procedure described in example 1 was repeated using glycolic acidandN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-morpholin-2-ylmethoxy]quinazolin-4-amine,but purifying the product by preparative HPLC, to give the titlecompound as a yellow solid in 48% yield; NMR spectrum (DMSO-d6)2.75-2.85 (m, 1H), 3.05-3.2 (m, 1H), 3.5-3.65 (m, 1H), 3.75-3.9 (m, 2H),4.0-4.2 (m, 3H), 4.25-4.4 (m, 2H), 4.55-4.7 (m, 1H), 5.3 (s, 2H),7.35-7.5 (m, 4H), 7.55-7.7 (m, 2H), 7.85-8.05 (m, 3H), 8.6 (d, 1H), 8.9(s, 1H); 11.8 (br s, 1H); Mass spectrum MH⁺ 536.5.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-morpholin-2-ylmethoxy]quinazolin-4-amineused as starting material was prepared as described in example 1(preparation of starting materials) using (2S)-morpholin-2-ylmethanol(obtained as described in Journal of Medicinal Chemistry 1998, 41(11),1934-1942) andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine asa solid in 46% yield; NMR spectrum (DMSO-d6) 1.47 (m, 1H), 1.69 (m, 2H),1.86 (m, 1H), 2.85 (m, 2H), 3.53 (m, 1H), 4.05 (dt, 1H), 4.31 (dd, 1H),5.27 (s, 2H), 7.12 (d, 1H), 7.23 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H),7.57 (d, 1H), 7.70 (t, 1H), 7.79 (dd, 1H), 7.86 (dt, 1H), 8.14 (d, 1H),8.50 (s, 1H), 8.58 (d, 1H), 10.55 (br s, 1H); Mass spectrum MH⁺ 478.

EXAMPLE 88N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-aminetrifluoroacetate

The procedure described in example 1 was repeated usingN,N-dimethylglycine andN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2S)-morpholin-2-ylmethoxy]quinazolin-4-amine(obtained as described in example 87, preparation of startingmaterials), but purifying the product by preparative HPLC, to give thetitle compound as a yellow solid in 38% yield; NMR spectrum (DMSO-d6)2.8 (s, 6H), 3.15-3.3 (m, 1H), 3.45-3.75 (m, 2H), 3.9-4.0 (m, 1H),4.05-4.2 (m, 3H), 4.3-4.45 (m, 3H), 4.6 (dd, 1H), 5.3 (s, 2H), 7.3-7.45(m, 4H), 7.55-7.7 (m, 2H), 7.85-8.05 (m, 3H), 8.6 (d, 1H), 8.85 (s, 1H);11.8 (br s, 1H); Mass spectrum MH⁺ 563.

EXAMPLE 892-((2S)-2-{[(4-{[3-Chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanolhydrochloride

The procedure described in example 21 was repeated using2-chloro-4-[(5-{[(2S)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol.The product obtained after chromatography was treated with 1 equivalentof 1M hydrogen chloride in ether to give the title compound as a solidin 35% yield; NMR spectrum (DMSO-d6) 1.4-1.55 (m, 1H), 1.6-1.8 (m, 4H),1.8-1.95 (m, 1H), 3.15-3.3 (m, 2H), 3.95 (d, 1H), 4.05-4.15 (m, 1H),4.3-4.4 (m, 1H), 4.9 (d, 1H), 5.15-5.25 (m, 1H), 5.4 (s, 2H), 7.4-7.6(m, 4H), 7.75 (s, 1H), 7.85 (s, 1H), 8.0 (t, 1H), 8.8 (s, 1H); 9.2 (s,1H), 10.7 (s, 1H); Mass spectrum MH⁺ 540.

The2-chloro-4-[(5-{[(2S)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as follows:

The procedure described in example 21 (preparation of startingmaterials) was repeated using (2S)-piperidin-2-ylmethanol (obtained asdescribed for the R-antipode in example 7, preparation of startingmaterials) and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol to give2-chloro-4-({5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenolas a light brown solid in 55% yield; NMR spectrum (DMSO-d6) 1.45-1.85(m, 5H), 1.95-2.05 (m, 1H), 2.85-3.0 (m, 1H), 3.35 (d, 1H), 3.7-3.8 (m,1H), 4.45-4.55 (m, 1H), 4.6-4.7 (m, 1H), 7.0 (d, 1H), 7.2 (d, 1H), 7.4(d, 1H), 7.55 (dd, 1H), 7.75 (t, 1H), 8.0 (d, 1H), 8.5 (s, 1H), 9.6 (brs, 2H), 10.1 (br s 1H).

The procedure described in example 21 (preparation of startingmaterials) was repeated using glycolic acid and2-chloro-4-({5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenol,but purifying the product by column chromatography, eluting with 0-10%methanol in DCM, to give2-chloro-4-[(5-{[(2S)-1-glycoloylpiperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolas a yellow foam in 70% yield; NMR spectrum (DMSO-d6) 1.35-1.5 (m, 1H),1.6-1.75 (m, 4H), 1.8-1.95 (m, 1H), 3.1-3.2 (m, 2H), 3.9-4.15 (m, 2H),4.6-4.7 (m, 2H), 5.1-5.2 (m, 1H), 6.95(d, 1H), 7.2-7.4 (m, 3H), 7.65-7.8(m, 2H), 8.4 (s, 1H), 9.6 (s, 1H); 10.0 (s, 1H).

EXAMPLE 90 N-[3-Chloro-4-(1,3-thiazol4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-aminehydrochloride

The procedure described in example 21 was repeated using2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)piperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenol.The product obtained after chromatography was treated with 1 equivalentof 1M hydrogen chloride in ether to give the title compound as a solidin 25% yield, NMR spectrum (DMSO-d6) 1.4-1.55 (m, 1H), 1.6-1.8 (m, 4H),1.9-2.0 (m, 1H), 2.6 (s, 3H), 2.75 (s, 3H), 3.15-3.3 (m, 2H), 3.95 (d,1H), 4.05-4.15 (m, 1H), 4.3-4.4 (m, 1H), 4.9 (d, 1H), 5.15-5.25 (m, 1H),5.4 (s, 2H), 7.4-7.6 (m, 4H), 7.75 (s, 1H), 7.85 (s, 1H), 8.0 (t, 1H),8.8 (s, 1H); 9.2 (s, 1H), 10.7 (s, 1H); Mass spectrum MH⁺ 567.

The2-chloro-4-[(5-{[(2S)-1-(N,N-dimethylglycyl)piperidin-2-yl]methoxy}quinazolin-4-yl)amino]phenolused as starting material was prepared as a solid in 25% yield using theprocedure described in example 21 (preparation of starting materials),but starting fromchloro-4-({5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-yl}amino)phenol(obtained as described in example 89, preparation of starting materials)and purifying the product by column chromatography, eluting with 0-10%methanol in DCM; NMR spectrum (DMSO-d6) 1.4-1.55 (m, 1H), 1.6-1.8 (m,4H), 1.85-1.95 (m, 1H), 3.5-3.6 (m, 1H), 3.8-3.9 (m, 1H), 4.0-4.15 (m,1H), 4.35-4.45 (m, 1H), 4.6-4.8 (m, 2H), 5.15-5.25 (m, 1H), 6.95(d, 1H),7.25-7.45 (m, 3H), 7.65-7.8 (m, 1H), 7.85 (s, 1H), 8.4 (s, 1H), 9.6 (s,1H); 10.0 (s, 1H).

EXAMPLE 91N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-aminehydrochloride

A solution of5-{[(2R)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine(200 mg), pyrrolidine (0.31 ml) and tetra-n-butylammonium iodide (70 mg)in DMA (15 ml) was heated at 100° C. for 2 hours. Volatile material wasremoved by evaporation and the residue was partitioned between DCM (10mL) and water (5 mL). The organic phase was separated, washed with water(5 ml) and saturated sodium chloride solution (5 ml), and purified bychromatography, eluting with 0-5% of 10:1 methanol/aqueous ammonia(0.880) in DCM. The appropriate fractions were combined andconcentrated, and the residue was treated with 1 equivalent of 1Mhydrogen chloride in ether to give the title compound as a solid (73mg); NMR spectrum (DMSO-d6) 1.2-1.3 (m, 1H), 1.45-1.55 (m, 1H), 1.7-2.05(m, 6H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 2H), 3.25-3.45 (m, 3H), 4.2 (s,2H), 4.45 (t, 1H), 4.55-4.65 (m, 1H), 5.3 (s, 2H), 7.25-7.4 (m, 4H),7.55 (d, 2H), 7.8-7.95 (m, 3H), 8.55 (d, 1H), 8.7 (s, 1H); 10.1 (br s,1H), 10.8 (br s, 1H); Mass spectrum MH⁺ 573.

The5-{[(2R)-1-(chloroacetyl)pyrolidin-2-yl]methoxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amineused as starting material was obtained as follows:

Chloroacetyl chloride (0.54 ml) was added to a solution ofN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(3.0 g, obtained as described example 1, preparation of startingmaterials), and N,N-diisopropylethylamine (1.1 ml) in DMF (60 ml) andthe mixture was stirred for 2 hours. Volatile material was removed byevaporation and the residue was triturated with water to give5-{[(2R)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine(2.95 g); NMR spectrum (DMSO-d6) 1.9-2.1 (m, 4H), 3.5-3.6 (m, 2H),4.2(dd, 1H), 4.35 (s, 2H), 4.4-4.5 (m, 1H), 4.55-4.65 (m, 1H), 5.3 (s,2H), 7.25-7.4 (m, 4H), 7.5-7.6 (m, 2H), 7.8 (t, 1H), 7.9 (t, 1H), 8.0(d, 1H); 8.55 (s, 1H), 8.6 (d, 1H), 10.25 (br s, 1H); Mass spectrum MH⁺538.5.

EXAMPLE 92N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl)-5-([(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine

Chloroacetyl chloride (46 μl, 0.62 mmol) was added dropwise to aice-cooled solution ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(240 mg, 0.54 mmol, Example 57 starting material) anddiisopropylethylamine (108 μl, 0.62 mmol) in DCM (2 ml). The mixture wasstirred at room temperature for 1 hour. Pyrrolidine (0.18 ml, 2.2 mmol)was added and the mixture was stirred at room temperature for 2 hours.After evaporation of the solvents to dryness, the residue was dissolvedin DMSO, filtered and purified on an HPLC column (C18, 5 microns, 19 mmdiameter, 100 mm length) of a preparative HPLC-MS system eluting with amixture of water and acetonitrile containing 2 g/l of ammonium formate(gradient). Additional purification by chromatography on silica gel(eluant: 8% 7N ammonia-methanol in DCM) afforded the title compound as awhite solid (112 mg, 37%); NMR spectrum (CDCl₃) 1.81 (m, 4H), 2.20-2.00(m, 4H), 2.29 (s, 3H), 2.53 (s, 3H), 2.64 (m, 2H), 2.69 (m, 2H), 3.26(d, 1H), 3.39 (d, 1H), 3.56 (m, 2H), 4.06 (t, 1H), 4.62 (m, 1H), 4.69(m, 1H), 6.91 (d, 1H), 7.14-7.07 (m, 3H), 7.47 (m, 2H), 7.64 (m, 2H),8.27 (s, 1H), 8.62 (s, 1H), 9.81 (s br, 1H); Mass spectrum: MH⁺ 553.

EXAMPLE 932-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure from example 57 was repeated usingN-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) and acetoxyacetyl chloride to give the titlecompound (102 mg, 43%); NMR spectrum (CDCl₃) 2.2-2.1 (m, 4H), 2.55 (s,3H), 3.27 (m, 1H), 3.46-3.37 (m, 2H), 4.17-4.07 (m, 3H), 4.54 (m, 1H),4.78 (m, 1H), 7.00 (m, 2H), 7.12 (d, 1H), 7.20 (d, 1H), 7.54 (m, 2H),7.66 (m, 1H), 7.97 (s, 1H), 8.31 (s, 1H), 8.64 (s, 1H), 9.93 (s br, 1H);Mass spectrum: MH⁺ 520.

TheN-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminewas made from 5-hydroxy-2-methylpyridine,3-chloro-4-fluoro-1-nitrobenzene, 4-chloro-5-fluoroquinazoline and(R)-2-pyrrolidinemethanol using a similar procedure as the one describedin example 57 starting material:

5-(2-chloro-4-nitrophenoxy)-2-methylpyridine (4.5 g, 93%); Massspectrum: MH⁺ 265.

3-chloro-4-[(6-methylpyridin-3-yl)oxy]aniline (1.33 g, 100%); Massspectrum: MH⁺ 235. The reaction was carried out in ethanol in thepresence of platinum oxide instead of palladium on charcoal.

N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-fluoroquinazolin-4-amine(1.83 g, 94%); Mass spectrum: MH⁺ 381.

N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(720 mg, 64%); Mass spectrum: MH⁺ 462.

EXAMPLE 942-[(2S)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol

The procedure from example 57 was repeated usingN-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) and acetoxyacetyl chloride to give the titlecompound (112 mg, 47%); NMR spectrum (CDCl₃) 2.2-2.1 (m, 4H), 2.55 (s,3H), 3.27 (m, 1H), 3.46-3.37 (m, 2H), 4.17-4.07 (m, 3H), 4.54 (m, 1H),4.78 (m, 1H), 7.00 (m, 2H), 7.12 (d, 1H), 7.20 (d, 1H), 7.54 (m, 2H),7.66 (m, 1H), 7.97 (s, 1H), 8.31 (s, 1H), 8.64 (s, 1H), 9.93 (s br, 1H);Mass spectrum: MH⁺ 520.

TheN-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminewas made fromN-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-fluoroquinazolin-4-amineand (S)-2-pyrrolidinemethanol following procedure of Example 57 startingmaterial:

N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(690 mg, 65%); Mass spectrum: MH⁺ 462.

EXAMPLE 952-((2R)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure from example 57 was repeated usingN-[3-chloro-4-(pyridin-3-yloxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) and acetoxyacetyl chloride to give the titlecompound (113 mg, 49%); NMR spectrum (CDCl₃) 2.3-2.1 (m, 4H), 3.46-3.37(m, 2H), 4.15-4.05 (m, 3H), 4.53 (m, 1H), 4.79 (m, 1H), 6.99 (m, 1H),7.09 (m, 1H), 7.29 (s, 2H); 7.50 (d, 1H), 7.67-7.58 (m, 2H), 8.03 (s,1H), 8.36 (s, 1H), 8.41 (s, 1H), 8.65 (s, 1H), 10.0 (s br, 1H); Massspectrum: MH⁺ 506.

TheN-[3-chloro-(pyridin-3-yloxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminewas made from 3-hydroxypyridine, 3-chloro-4-fluoro-1-nitrobenzene,4-chloro-5-fluoroquinazoline and (R)-2-pyrrolidinemethanol using asimilar procedure as the one described in example 57 starting material:

3-(2-chloro-4-nitrophenoxy)pyridine (4.8 g, 85%); Mass spectrum: MH⁺251.

3-chloro-4-(pyridin-3-yloxy)aniline (2.28 g, 58%); Mass spectrum: MH⁺235. The reaction was carried out in ethanol in the presence of platinumoxide instead of palladium on charcoal and after work-up, the residuewas purified by chromatography on silica gel (eluant: 5% methanol inDCM).

N-[3-chloro-4-(pyridin-3-yloxy)phenyl]-5-fluoroquinazolin-4-amine (1.7g, 81%); Mass spectrum: MH⁺ 367.

N-[3-chloro-4-(pyridin-3-yloxy)phenyl]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-5-amine;Mass spectrum: MH⁺ 448.

EXAMPLE 962-((2S)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol

The procedure from example 57 was repeated usingN-[3-chloro-4-(pyridin-3-yloxy)phenyl]-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) and acetoxyacetyl chloride to give the titlecompound (113 mg, 49%); NMR spectrum (CDCl₃) 2.3-2.1 (m, 4H), 3.46-3.37(m, 2H), 4.15-4.05 (m, 3H), 4.53 (m, 1H), 4.79 (m, 1H), 6.99 (m, 1H),7.09 (m, 1H), 7.29 (s, 2H); 7.50 (d, 1H), 7.67-7.58 (m, 2H), 8.03 (s,1H), 8.36 (s, 1H), 8.41 (s, 1H), 8.65 (s, 1H), 10.0 (s br, 1H); Massspectrum: MH⁺ 506.

TheN-[3-chloro-4-(pyridin-3-yloxy)phenyl]-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-aminewas made fromN-[3-chloro-4-(pyridin-3-yloxy)phenyl]-5-fluoroquinazolin-4-amine and(s)-2-pyrrolidinemethanol following procedure of Example 57 startingmaterial:

N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine(448 mg, 61%); Mass spectrum: MH⁺ 462.

EXAMPLE 972-[(3R)-3-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)morpholin-4-yl]-2-oxoethanol

The procedure from example 57 was repeated usingN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(3R)-morpholin-3-ylmethoxy]quinazolin-4-amine-(250mg, 0.57 mmol) and acetoxyacetyl chloride to give the title compound (70mg, 24%); NMR spectrum (CDCl₃) 2.29 (s, 3H), 2.53 (s, 3H), 3.14 (s br,1H), 3.25 (d, 1H), 3.57-3.49 (m, 2H), 3.85-3.78 (m, 2H), 4.06 (dd, 1H),4.20 (m, 2H), 4.43 (m, 1H), 4.59 (m, 1H), 5.03 (m, 1H), 6.91 (d, 1H),6.96 (d, 1H), 7.09 (d, 1H), 7.17 (m, 1H), 7.34 (m, 1H), 7.49 (m, 2H),7.65 (t, 1H), 8.28 (s, 1H), 8.57 (s, 1H), 9.43 (s br, 1H); Massspectrum: MH⁺ 516.

TheN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(3R)-morpholin-3-ylmethoxy]quinazolin-4-amineused as starting material was made from5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amineand (3S)-morpholin-3-ylmethanol (J. Chem. Soc. Perkin Trans. 1,2577-2580 (1985)) according to procedure from example 57 startingmaterial:

N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(3R)-morpholin-3-ylmethoxy]quinazolin-4-amine(320 mg, 50%); Mass spectrum: MH⁺ 548.

EXAMPLE 982-((3R)-3-{[(4-{[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol

The procedure from example 57 was repeated usingN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-morpholin-3-ylmethoxy]quinazolin-4-amine(250 mg, 0.52 mmol) and acetoxyacetyl chloride to give the titlecompound (55 mg, 20%); NMR spectrum (CDCl₃) 3.17 (m, 1H), 3.25 (d, 1H),3.55 (m, 2H), 3.80 (m, 2H), 4.08 (dd, 1H), 4.20 (m, 2H), 4.41 (m, 1H),4.59 (t, 1H), 5.01 (m, 1H), 5.30 (s, 2H), 6.95 (d, 1H), 7.03 (d, 1H),7.25 (m, 1H), 7.39 (dd, 1H), 7.51 (d, 1H), 7.70-7.63 (m, 3H), 7.75 (m,1H), 8.56 (s, 1H), 8.59 (d, 1H), 9.43 (s br, 1H); Mass spectrum: MH⁺536.

TheN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-morpholin-3-ylmethoxy]quinazolin-4-amineused as starting material was made fromN-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amineand (3S)-morpholin-3-ylmethanol (J. Chem. Soc. Perkin Trans. 1,2577-2580 (1985)) according to procedure from example 57 startingmaterial:

N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(3R)-morpholin-3-ylmethoxy]quinazolin-4-amine(396 mg, 63%); Mass spectrum: MH⁺ 478.

EXAMPLE 992-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure from Example 1 was repeated usingN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) except that after evaporation of the solvents, theresidue was injected on an HPLC column (C18, 5 microns, 19 mm diameter,100 mm length) of a preparative HPLC-MS system eluting with a mixture ofwater and acetonitrile containing 2 g/l of ammonium formate (gradient)to give the title compound (115 mg, 51%); NMR Spectrum: (DMSOd₆ andCF₃CO₂D) 1.45 (m, 1H), 1.68 (m, 4H), 1.87 (m, 1H), 2.28 (s, 3H), 2.71(s, 3H), 3.24 (m, 1H), 3.56 (m, 1H), 3.94 (m, 1H), 4.11 (m, 1H), 4.92(t, 1H), 5.28 (m, 1H), 7.21 (d, 1H), 7.44 (d, 1H), 7.7-7.5 (m, 3H), 7.94(d, 1H), 8.11-8.04 (m, 2H), 8.72 (s, 1H), 8.85 (s, 1H); Mass spectrum:MH⁺ 514.

TheN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-amineused as starting material was made from5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amineand (2R)-piperidin-2-ylmethanol according to procedure from example 57starting material:N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2R)-piperidin-2-ylmethoxy]quinazolin-4-amine(415 mg, 73%); Mass spectrum: MH⁺ 456.

EXAMPLE 1002-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol

The procedure from Example 1 was repeated usingN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-amine(200 mg, 0.45 mmol) except that after evaporation of the solvents, theresidue was injected on an HPLC column (C18, 5 microns, 19 mm diameter,100 mm length) of a preparative HPLC-MS system eluting with a mixture ofwater and acetonitrile containing 2 g/l of ammonium formate (gradient)to give the title compound (100 mg, 45%); NMR Spectrum: (DMSOd₆ andCF₃CO₂D) 1.45 (m, 1H), 1.68 (m, 4H), 1.87 (m, 1H), 2.28 (s, 3H), 2.71(s, 3H), 3.24 (m, 1H), 3.56 (m, 1H), 3.94 (m, 1H), 4.11 (m, 1H), 4.92(t, 1H), 5.28 (m, 1H), 7.21 (d, 1H), 7.44 (d, 1H), 7.7-7.5 (m, 3H), 7.94(d, 1H), 8.11-8.04 (m, 2H), 8.72 (s, 1H), 8.85 (s, 1H); Mass spectrum:MH⁺ 514.

TheN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-amineused as starting material was made from5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amineand (2S)-piperidin-2-ylmethanol according to procedure from example 57starting material:

N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-[(2S)-piperidin-2-ylmethoxy]quinazolin-4-amine(391 mg, 52%); Mass spectrum: MH⁺ 456.

EXAMPLE 1012-[(2R)-4-methyl-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperazin-1-yl]-2-oxoethanol

A mixture ofN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-amine(200 mg, 0.43 mmol), glycolic acid (36 mg, 0.47 mmol),diisopropylethylamine (0.22 ml, 1.28 mmol) and HATU (179 mg, 0.47 mmol)in DMF (2 ml) was stirred at room temperature for 16 hours. More HATU(36 mg) and glycolic acid (8 mg) were added. The mixture was stirred for16 hours more. After evaporation of the solvents under high vacuum, theresidue was taken in dichloromethane. The resulting solution was washedwith saturated aqueous ammonium chloride, saturated aqueous sodiumbicarbonate, dried over magnesium sulfate. After evaporation of thesolvents, the residue was purified by chromatography on silica gel(eluant: 4% to 7% 7N ammonia-methanol in dichloromethane) to give thetitle compound (132 mg, 60%) as a beige solid; NMR spectrum (CDCl₃) 2.03(m, 1H), 2.23 (s, 3H), 2.28 (m, 1H), 2.30 (s, 3H), 2.54 (s, 3H), 2.77(m, 1H), 3.01 (m, 1H), 3.15 (m, 1H), 3.34 (m, 1H), 3.47 (m, 1H), 4.07(dd, 1H), 4.20 (dd, 1H), 4.37 (dd, 1H), 4.62 (m, 1H), 5.20 (m, 1H), 6.92(d, 1H), 6.97 (d, 1H), 7.10 (d, 1H), 7.18 (m, 1H), 7.32 (m, 1H), 7.45(s, 1H), 7.52 (m, 1H), 7.65 (m, 1H), 8.29 (s, 1H), 8.56 (s, 1H), 9.62 (sbr, 1H); Mass spectrum: MH⁺ 529.

TheN-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-amineused as starting material was made from5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amineand [(2R)-4-methylpiperazin-2-yl]methanol (Example 36 starting material)according to procedure from Example 57 starting material:

N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-4-methylpiperazin-2-yl]methoxy}quinazolin-4-amine(536 mg, 33%); Mass spectrum: MH⁺ 471.

1. A quinazoline derivative of the Formula I:

wherein: R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and whereinadjacent carbon atoms in any (2-6C)alkylene chain within a R¹substituent are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R³), CO, CON(R³), N(R³)CO,SO₂N(R³) and N(R³)SO₂, wherein R³ is hydrogen or (1-6C)alkyl, andwherein any CH₂ or CH₃ group within a R¹ substituent optionally bears oneach said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents, or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino; Y is selected from hydrogen,halogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl; ais 0, 1, 2 or 3 or 4; each R², which may be the same or different, isselected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyl and(2-4C)alkynyl; X² is a direct bond or is selected from O, S, OC(R⁴)₂,SC(R⁴)₂, SO, SO₂, N(R⁴), CO and N(R⁴)C(R⁴)₂ wherein each R⁴ is, whichmay be the same or different, is selected from hydrogen or (1-6C)alkyl,and Q² is aryl or heteroaryl, and wherein Q² optionally bears one ormore substituents (for example 1, 2 or 3), which may be the same ordifferent, selected from halogeno, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵ wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶),wherein R⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl, N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl, andwherein any CH₂ or CH₃ group within —X²-Q² optionally bears on each saidCH₂ or CH₃ one or more (for example 1, 2, or 3) halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,(1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; X¹ is a directbond or C(R⁷)₂, wherein each R⁷, which may be the same or different, isselected from hydrogen and (1-4C)alkyl; ring Q¹ is a 4, 5, 6 or 7membered saturated or partially unsaturated heterocyclyl groupcontaining 1 nitrogen heteroatom and optionally 1 or 2 additionalheteroatoms selected from O, S and N, and which ring is linked to thegroup X¹ by a ring carbon; X³ is a group of the formula:—(CR⁸R⁹)_(p)-(Q³)_(m)-(CR¹⁰R¹¹)_(q)— wherein m is 0 or 1, p is 0, 1, 2,3 or 4 and q is 0, 1, 2, 3 or 4, each of R⁸, R⁹, R¹⁰ and R¹¹, which maybe the same or different, is selected from hydrogen and (1-6C)alkyl; andQ³ is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene; Z isselected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula:Q⁴-X⁵— wherein X⁵ is a direct bond or is selected from O, N(R¹²), SO₂and SO₂N(R¹²), wherein R¹² is hydrogen or (1-6C)alkyl, and Q⁴ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl, provided that when X⁵ is a direct bond, Q⁴ isheterocyclyl, and provided that when m, p and q are all 0, then Z isheterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylenechain within a Z substituent are optionally separated by the insertioninto the chain of a group selected from O, S, SO, SO₂, N(R¹³), CO, —C═C—and —C≡C— wherein R¹³ is hydrogen or (1-6C)alkyl, and wherein andwherein any CH₂ or CH₃ group within any Z, X¹ or X³ group, other than aCH₂ group within a heterocyclyl ring, optionally bears on each said CH₂or CH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,and wherein any heterocyclyl group represented by Q¹ or within a Zsubstituent optionally bears one or more (for example 1, 2 or 3)substituents, which may be the same or different, selected fromhalogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl,mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴ wherein X⁶ is a direct bond or is selected from O, CO, SO₂ andN(R¹⁵), wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ ishalogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl, and wherein any heterocyclylgroup represented by Q¹ or within a Z substituent optionally bears 1 or2 oxo or thioxo substituents; or a pharmaceutically acceptable saltthereof.
 2. A quinazoline derivative of the Formula I as defined inclaim 1, wherein R¹ is selected from hydrogen, hydroxy, (1-6C)alkoxy,(3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein anyCH₂ or CH₃ group within a R¹ substituent optionally bears on each saidCH₂ or CH₃ group one or more fluoro or chloro substituents, or asubstituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylaminoand di-[(1-4C)alkyl]amino.
 3. A quinazoline derivative of the Formula Ias defined in claim 1 or claim 2, wherein R¹ is selected from hydrogen,methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy,2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.
 4. A quinazolinederivative of the Formula I as defined in any one of claims 1 to 3,wherein R¹ is hydrogen.
 5. A quinazoline derivative of the Formula I asdefined in any one of claims 1 to 4, wherein Y is selected fromhalogeno, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl. 6.A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 5, wherein Y is selected from halogeno and (1-4C)alkyl.
 7. Aquinazoline derivative of the Formula I as defined in any one of claims1 to 6, wherein Y is selected from chloro and methyl.
 8. A quinazolinederivative of the Formula I as defined in any one of claims 1 to 7,wherein a is
 0. 9. A quinazoline derivative of the Formula I as definedin any one of claims 1 to 8, wherein X² is selected from O, S andOC(R⁴)₂ wherein each R⁴ is, independently, hydrogen or (1-4C)alkyl. 10.A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 9, wherein X² is selected from O, S and OCH₂.
 11. Aquinazoline derivative of the Formula I as defined in any one of claims1 to 10, wherein X² is O.
 12. A quinazoline derivative of the Formula Ias defined in any one of claims 1 to 10, wherein X² is OCH₂.
 13. Aquinazoline derivative of the Formula I as defined in any one of claims1 to 12, wherein Q² is selected from phenyl and a 5- or 6-memberedmonocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroatomsindependently selected from oxygen, nitrogen and sulfur, and wherein Q²optionally bears one or more substituents, which may be the same ordifferent, selected from halogeno, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, sulfamoyl, formyl, mercapto, (1-6C)alkyl,(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl,(1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, anda group of the formula:—X⁴—R⁵ wherein X⁴ is a direct bond or is selected from O, CO and N(R⁶),wherein R⁶ is hydrogen or (1-6C)alkyl, and R⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl,(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl,N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, sulfamoyl(1-6C)alkyl,N-(1-6C)alkylsulfamoyl(1-6C)alkyl, N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl,(2-6C)alkanoyloxy-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl, andwherein any CH₂ or CH₃ group within Q² optionally bears on each said CH₂or CH₃ one or more halogeno or (1-6C)alkyl substituents or a substituentselected from hydroxy, cyano, amino, (1-4C)alkoxy, (1-4C)alkylamino anddi-[(1-4C)alkyl]amino.
 14. A quinazoline derivative of the Formula I asdefined in any one of claims 1 to 13, wherein Q² is selected fromphenyl, pyridyl, pyrazinyl, 1,3-thiazolyl, 1H-imidazolyl, 1H-pyrazolyl,1,3-oxazolyl and isoxazolyl, and wherein Q² optionally bears one or moresubstituents, which may be the same or different, as defined in claim13.
 15. A quinazoline derivative of the Formula I as defined in any oneof claims 1 to 14, wherein Q² is selected from phenyl, pyridyl,pyrazinyl, 1,3-thiazolyl and isoxazolyl, and wherein Q² optionally bearsone or more substituents, which may be the same or different, as definedin claim
 13. 16. A quinazoline derivative of the Formula I as defined inany one of claims 1 to 15, wherein Q² is selected from phenyl,2-pyridyl, 3-pyridyl, 2-pyrazinyl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl,1,3-thiazol-5-yl and 3-isoxazolyl, and wherein Q² optionally bears oneor more substituents, which may be the same or different, ashereinbefore defined in claim
 13. 17. A quinazoline derivative of theFormula I as defined in any one of claims 13 to 16, wherein Q²optionally bears one or more substituents, which may be the same ordifferent, selected from halogeno, hydroxy, cyano, carboxy, nitro,amino, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl,(1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl,(2-4C)alkanoyl, N-(1-4C)alkylamino, N,N-di-[(1-4C)alkyl]amino,(1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyloxy, (2-4C)alkanoylamino,N-(1-4C)alkyl-(2-4C)alkanoylamino, halogeno-(1-4C)alkyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl,carboxy-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyland N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl.
 18. A quinazoline derivativeof the Formula I as defined in any one of claims 13 to 16, wherein Q²optionally bears one or more substituents, which may be the same ordifferent, selected from fluoro, chloro, bromo, hydroxy, carboxy, cyano,nitro, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl,ethynyl, 2-propynyl, methylthio, methylsulfinyl, methylsulfonyl, acetyl,propionyl methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino,N-methyl-N-ethylamino methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetoxy, acetamido,fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, hydroxymethyl,2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, cyanomethyl,2-cyanoethyl, carboxymethyl, 2-carboxymethyl, aminomethyl,methylaminomethyl, ethylaminomethyl, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N-methyl-N-ethylaminomethyl, 2-aminoethyl,2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(N,N-dimethylamino)ethyl,2-(N,N-diethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl,carbamoylmethyl, N-methylcarbamoylmethyl andN,N-dimethylcarbamoylmethyl.
 19. A quinazoline derivative of the FormulaI as defined in any one of claims 13 to 16, wherein Q² optionally bears1, 2, or 3 substituents, which may be the same or different, selectedfrom fluoro, chloro, hydroxy, cyano, nitro, (1-4C)alkyl and(1-4C)alkoxy.
 20. A quinazoline derivative of the Formula I as definedin any one of claims 1 to 19, wherein Q² is selected from2-fluorophenyl, 3-fluorophenyl, 2-pyridyl, 3-pyridyl,6-methylpyrid-2-yl, 6-methylpyrid-3-yl, 2-pyrazinyl, 1,3-thiazol-2-yl,1,3-thiazol-4-yl, 1,3-thiazol-5-yl and 5-methyl-3-isoxazolyl.
 21. Aquinazoline derivative of the Formula I as defined in any one of claims1 to 20, wherein the group —X²-Q² is selected from pyrid-2-ylmethoxy,1,3-thiazol-4-ylmethoxy, (5-methylisoxazol-3-yl)methoxy,1,3-thiazol-5-ylmethoxy, pyrazin-2-ylmethoxy,(6-methylpyrid-2-yl)methoxy, (2-fluorobenzyl)oxy, (3-fluorobenzyl)oxy,(6-methylpyrid-3-yl)oxy, 1,3-thiazol-2-ylmethoxy and pyrid-3-yloxy. 22.A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 21, wherein X¹ is selected from a direct bond and C(R⁷)₂,wherein each R⁷, which may be the same or different, is selected fromhydrogen and methyl.
 23. A quinazoline derivative of the Formula I asdefined in any one of claims 1 to 22, wherein X¹ is selected from adirect bond, CH₂ and CH(CH₃).
 24. A quinazoline derivative of theFormula I as defined in any one of claims 1 to 23, wherein Q¹ is a 5 or6 membered saturated heterocyclyl group containing 1 nitrogen heteroatomand optionally 1 or 2 additional heteroatoms independently selected fromoxygen, nitrogen and sulfur, and which ring is linked to the group X¹ bya ring carbon.
 25. A quinazoline derivative of the Formula I as definedin any one of claims 1 to 24, wherein Q¹ is selected from azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, and wherein Q¹ is linked to the group X¹—O by a ringcarbon atom, and wherein Q¹ optionally bears one or more substituents,which may be the same or different, selected from halogeno,trifluoromethyl, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl, and whereinany heterocyclyl group within Q¹ optionally bears an oxo substituent.26. A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 25, wherein Q¹ is selected from pyrrolidinyl, piperidinyl,piperazinyl and morpholinyl, and wherein Q¹ is linked to the group X¹—Oby a ring carbon atom, and wherein Q¹ optionally bears one or moresubstituents, which may be the same or different, selected fromhalogeno, trifluoromethyl, hydroxy, carbamoyl, (1-4C)alkyl,(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,and wherein any heterocyclyl group within Q¹ optionally bears an oxosubstituent.
 27. A quinazoline derivative of the Formula I as defined inany one of claims 1 to 26, wherein Q¹ is selected from azetidin-2-yl,azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-2-yl,morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl, piperazin-2-yl, piperazin-3-yl, 2-, 3-or 4-homopiperidinyl, 2, 3, 5, 6 or 7-homopiperazinyl, and wherein Q¹ islinked to the group X¹—O by a ring carbon atom, and wherein Q¹optionally bears one or more substituents, which may be the same ordifferent, selected from fluoro, chloro, hydroxy, carbamoyl,(1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl andN,N-di-[(1-4C)alkyl]carbamoyl, and wherein any heterocyclyl group withinQ¹ optionally bears an oxo substituent.
 28. A quinazoline derivative ofthe Formula I as defined in any one of claims 1 to 27, wherein Q¹ isselected from pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-2-yl,morpholin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-2-yl and piperazin-3-yl, and wherein Q¹ is linked to the groupX¹—O by a ring carbon atom, and wherein Q¹ optionally bears one or moresubstituents, which may be the same or different, selected from fluoro,chloro, hydroxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl, and whereinany heterocyclyl group within Q¹ optionally bears an oxo substituent.29. A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 28, wherein X³ is a group of the formula:—(CR⁸R⁹)_(p)-(Q³)_(m)-(CR¹⁰R¹¹)_(q)—wherein m, p and q are not all 0,and wherein when m is 0 and the sum of p and q is 6, then Z is not thegroup Q⁴-X⁵— wherein X⁵ is a direct bond and Q⁴ is heterocyclyl, andwherein when m is 0 and the sum of p and q is 1, 2, 3, 4 or 5, then Z isnot amino, (1-6C)alkylamino or di-[(1-6C)alkyl]amino or the group Q⁴-X⁵—wherein X⁵ is a direct bond and Q⁴ is heterocyclyl.
 30. A quinazolinederivative of the Formula I as defined in any one of claims 1 to 28,wherein X³ is selected from a group of the formula-(Q³)_(m)-(CR¹⁰R¹¹)_(q)— and a group of the formula—(CR⁸R⁹)_(q)-(Q³)_(m)-, wherein m is 0 or 1, q is 1, 2, 3 or 4, and Q³,R⁸, R⁹, R¹⁰ and R¹¹ are as defined in claim
 1. 31. A quinazolinederivative of the Formula I as defined in claim 30, wherein X³ is agroup of the formula -Q³-, wherein Q³ is as defined in claim
 1. 32. Aquinazoline derivative of the Formula I as defined in any one of claims1 to 30, wherein X³ is a group of the formula —(CR⁸R⁹)_(q)—, wherein qis 1, 2, 3 or 4 and each of R⁸ and R⁹, which may be the same ordifferent, is selected from hydrogen and (1-6C)alkyl, and wherein anyCH₂ or CH₃ group within an X³ group, optionally bears on each said CH₂or CH₃ group one or more halogeno substituents, and wherein any CH₂group which is attached to 2 carbon atoms or any CH₃ group which isattached to a carbon atom within a X³ substituent optionally bears oneach said CH₂ or CH₃ group a substituent selected from hydroxy and(1-6C)alkoxy.
 33. A quinazoline derivative of the Formula I as definedin any one of claims 1 to 30, wherein X³ is selected from a group of theformula —CH₂—, —CH₂CH₂—, —(CHR⁸)—, —(CHR⁸CH₂)— and —(CH₂CHR⁸)—, whereinR⁸ is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and(1-3C)alkoxy-(1-4C)alkyl.
 34. A quinazoline derivative of the Formula Ias defined in any one of claims 1 to 33, wherein Z is selected fromhydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy,(1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino andN-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:Q⁴-X⁵—wherein X⁵ is a direct bond or is selected from O, N(R¹²), SO₂ andSO₂N(R¹²), wherein R¹² is hydrogen or (1-6C)alkyl, and Q⁴ is(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl, provided that when X⁵ is a direct bond, Q⁴ isheterocyclyl, and provided that when m, p and q are all 0, then Z isheterocyclyl, and wherein any heterocyclyl group in Z is a fullysaturated 4, 5, 6 or 7-membered monocyclic heterocyclyl group containing1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, andwherein any CH₂ or CH₃ group within a Z group, other than a CH₂ groupwithin a heterocyclyl ring, optionally bears on each said CH₂ or CH₃group one or more halogeno or (1-6C)alkyl substituents or a substituentselected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl,(2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl;(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,and wherein any heterocyclyl group within a Z substituent optionallybears one or more substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴ wherein X⁶ is a direct bond or is selected from O, CO, SO₂ andN(R¹⁵), wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ ishalogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl, and wherein any heterocyclylgroup within a Z substituent optionally bears 1 or 2 oxo substituents.35. A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 34, wherein Z is selected from hydroxy, amino,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of theformula:Q⁴-X⁵—wherein X⁵ is a direct bond or is selected from O and N(R¹²),wherein R¹² is hydrogen or (1-6C)alkyl, and Q⁴ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl orheterocyclyl-(1-4C)alkyl, provided that when X⁵ is a direct bond, Q⁴ isheterocyclyl, and provided that when m, p and q are all 0, then Z isheterocyclyl, and wherein any heterocyclyl group in Z is selected fromtetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl,oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, whichheterocyclyl group may be carbon or nitrogen linked to the group towhich it is attached, and wherein any CH₂ or CH₃ group within a Z group,other than a CH₂ group within a heterocyclyl ring, optionally bears oneach said CH₂ or CH₃ group one or more halogeno or (1-6C)alkylsubstituents or a substituent selected from hydroxy, cyano, amino,carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,(1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,and wherein any heterocyclyl group within a Z substituent optionallybears one or more substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl,(2-6C)alkanoyloxy and from a group of the formula:—X⁶—R¹⁴ wherein X⁶ is a direct bond or is selected from O, CO, SO₂ andN(R¹⁵), wherein R¹⁵ is hydrogen or (1-4C)alkyl, and R¹⁴ ishalogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl andN,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl, and wherein any heterocyclylgroup within a Z substituent optionally bears 1 or 2 oxo substituents.36. A quinazoline derivative of the Formula I as defined in any one ofclaims 1 to 35, wherein Z is selected from hydroxy, methoxy, ethoxy,2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino,N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino,N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino,N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino,N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino,tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclylgroup within Z optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyland (1-4C)alkoxy.
 37. A quinazoline derivative selected from one or moreof the following:2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholinyl)-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-4-[(dimethylamino)acetyl]morpholin-3-yl}methoxy)quinazolin-4-amine;2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ol;1-[((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)carbonyl]cyclopropanol;3-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol;(2S)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(ethoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;2-{(3S)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}oxy)quinazolin-4-amine;2-{(3R)-3-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]pyrrolidin-1-yl}-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}quinazolin-4-amine;N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;N-{3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;2-[(2R)-2-({[4-({3-chloro-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;N-[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-5-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-{(3S)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;2-{(3R)-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]piperidin-1-yl}-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[dimethylamino)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;(2R)-1-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-1-oxopropan-2-ol;2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}-4-methylpiperazin-1-yl)-2-oxoethanol;2-((2R)-2-{(1S)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2R)-2-{(1R)-1-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}pyrrolidin-1-yl)-2-oxoethanol;2-[(2S)-2-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;2-[(2S)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;2-[(2S)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2S)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;N-{3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;N-{3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;N-[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)quinazolin-4-amine;2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-[(2R)-2-({[4-({3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-[(2R)-2-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-((2R)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-((2R)-2-{[(4-{[3-chloro-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;5-({(2R)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;5-({(2S)-1-[(dimethylamino)acetyl]pyrrolidin-2-yl}methoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine;2-(4-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-1-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-(4-{[(4-{[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-[4-({[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-[4-({[4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-((2S)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2S)-2-{[(4-{[3-methyl(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2R)-2-{[(4-{[3-methyl-4-(pyrazin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2R)-2-{[(4-{[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-[(2R)-2-({[4-({3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-{3-methyl-4-[(5-methylisoxazol-3-yl)methoxy]phenyl}quinazolin-4-amine;5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine;5-{[(2R)-1-(methoxyacetyl)pyrrolidin-2-yl]methoxy}-N-[3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine;2-((2R)-2-{[(4-{[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-((3R)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-[(3R)-3-({[4-({3-chloro[(5-methylisoxazol-3-yl)methoxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-((3S)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-((3S)-3-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3R)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine;2-((3S-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(3S)-1-[(dimethylamino)acetyl]pyrrolidin-3-yl}methoxy)quinazolin-4-amine;(N-[3-chloro-(pyridin-2-ylmethoxy)phenyl]-5-{[(3S)-1-(methoxyacetyl)pyrrolidin-3-yl]methoxy}quinazolin-4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2R)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine;2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;2-(S)-2-{[(4-{[3-chloro-4-pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholin-4-yl)-2-oxoethanol;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-({(2S)-4-[(dimethylamino)acetyl]morpholin-2-yl}methoxy)quinazolin-4-amine;2-((2S)-2-{[(4-{[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}piperidin-1-yl)-2-oxoethanol;N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]-5-({(2S)-1-[(dimethylamino)acetyl]piperidin-2-yl}methoxy)quinazolin-4-amine;N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-{[(2R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazolin-4-amine;2-[(2R)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;2-[(2S)-2-({[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)pyrrolidin-1-yl]-2-oxoethanol;2-((2R)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-((2S)-2-{[(4-{[3-chloro-4-(pyridin-3-yloxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}pyrrolidin-1-yl)-2-oxoethanol;2-[(3R)-3-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)morpholin-4-yl]-2-oxoethanol;2-((3R)-3-{[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]methyl}morpholinyl)-2-oxoethanol;2-[(2R)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;2-[(2S)-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperidin-1-yl]-2-oxoethanol;and2-[(2R)-4-methyl-2-({[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}methyl)piperazin-1-yl]-2-oxoethanol;or a pharmaceutically acceptable salt thereof.
 38. A pharmaceuticalcomposition which comprises a quinazoline derivative of the Formula I,or a pharmaceutically acceptable salt thereof, as defined in any one ofclaims 1 to 37 in association with a pharmaceutically-acceptable diluentor carrier.
 39. A quinazoline derivative of the Formula I, or apharmaceutically acceptable salt thereof, as defined in any one ofclaims 1 to 37 for use as a medicament.
 40. A quinazoline derivative ofthe Formula I, or a pharmaceutically acceptable salt thereof, as definedin any one of claims 1 to 37 for use in the production of ananti-proliferative effect which effect is produced alone or in part byinhibiting erbB2 receptor tyrosine kinase in a warm-blooded animal suchas man.
 41. A quinazoline derivative of the Formula I, or apharmaceutically acceptable salt thereof, as defined in any one ofclaims 1 to 37 for use in the production of an erbB2 receptor tyrosinekinase inhibitory effect in a warm-blooded animal such as man.
 42. Aquinazoline derivative of the Formula I, or a pharmaceuticallyacceptable salt thereof, as defined in any one of claims 1 to 37 for usein the production of a selective erbB2 receptor tyrosine kinaseinhibitory effect in a warm-blooded animal such as man.
 43. A processfor the preparation of a quinazoline derivative of the Formula I, or apharmaceutically acceptable salt thereof, as defined in claim 1 whichcomprises: (a) the coupling, conveniently in the presence of a suitablebase, of a quinazoline of the formula II:

II wherein R¹, R², X¹, X², Y, a, Q¹ and Q² have any of the meaningsdefined in any one of claims 1 to 37 except that any functional group isprotected if necessary, with a carboxylic acid of the formula III, or areactive derivative thereof:Z-X³—COOH  III wherein Z and X³ have any of the meanings defined in anyone of claims 1 to 37 except that any functional group is protected ifnecessary; or (b) for the preparation of those compounds of the FormulaI wherein X² is OC(R⁴)₂, SC(R⁴)₂ or N(R⁴)C(R⁴)₂, the reaction,conveniently in the presence of a suitable base, of a quinazoline of theformula IV:

wherein X^(2a) is O, S or N(R⁴) and R¹, R², X¹, X², X³, Z, Y, a and Q¹have any of the meanings defined in any one of claims 1 to 37 exceptthat any functional group is protected if necessary, with a compound ofthe formula V:Q²-C(R⁴)₂-L¹  V wherein L¹ is a suitable displaceable group and Q² andR⁴ have any of the meanings defined in any one of claims 1 to 37 exceptthat any functional group is protected if necessary; (c) the coupling ofa quinazoline of the formula VI:

wherein L¹ is a suitable displaceable group and R¹, R², X¹, X², X³, Y,a, Q¹ and Q² have any of the meanings defined in any one of claims 1 to37 except that any functional group is protected if necessary, with acompound of the formula VII, or a reactive derivative thereof:Z-H  VII wherein Z has any of the meanings defined in any one of claims1 to 37 except that any functional group is protected if necessary; or(d) for the preparation of those compounds of the Formula I wherein X²is O and Q² is 2-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,2-pyrazinyl or 3-pyridazinyl, the reaction, conveniently in the presenceof a suitable base and a suitable catalyst, of a quinazoline of theformula IV:

wherein X^(2a) is O and wherein R¹, R², X¹, X³, Z, Y, a and Q¹ have anyof the meanings defined in any one of claims 1 to 37 except that anyfunctional group is protected if necessary, with 2-bromopyridine,4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine,2-chloropyrazine or 3-chloropyridazine; and thereafter, if necessary:(i) converting a quinazoline derivative of the formula I into anotherquinazoline derivative of the formula I; (ii) removing any protectinggroup that is present by conventional means; (iii) forming apharmaceutically acceptable salt.